TNF and interruption
of apoptosis (programmed cell death)
seem to play an important role in persistence
of most (all?)
chronic INTRACELLULAR INFECTIONs
- if you have additional references
or comments, please send a note to Marie Kroun
-
Hostile takeovers: viral appropriation of the NF-kappaB
pathway.
Hiscott J et al. J Clin Invest 2001
Jan;107(2):143-51. PubMed:
11160127 PDF
Transcriptional regulators of the NF-kB/IkB family promote the expression of well
over 100 target genes, the majority of which participate in the host
immune response (1). These proteins include a multitude of
cytokines and chemokines, receptors required for
immune recognition, proteins involved in antigen presentation, and
adhesion receptors involved in transmigration across blood vessels
walls. Because of this extensive role in immune action, NF-kB has been termed the central mediator of the immune
response. Gene knockout and other studies establish roles for
NF-kB in the ontogeny of the immune system
but also demonstrate that NF-kB
participates at multiple steps during oncogenesis (2) and the regulation of programmed cell
death (3).
For several reasons, the NF-kB pathway provides
an attractive target to viral pathogens. Activation of NF-kB is a rapid, immediate early (IE) event that
occurs within minutes after exposure to a relevant inducer, does not
require de novo protein synthesis, and results in a strong
transcriptional stimulation of several early viral as well as
cellular genes. In this review, we will describe strategies that
viruses have evolved to modulate the NF-kB
pathway, to enhance viral replication, host cell survival, and
evasion of immune responses. Activation of NF-kB
constitutes an obvious target because many of its target genes —
growth factors, cytokines and their receptors, and proto-oncogenes — profoundly influence the host cell
cycle. In addition, some viruses exploit the antiapoptotic
properties of NF-kB to evade the host defense mechanisms that limit replication by killing
infected cells, or conversely to trigger apoptosis as a mechanism to
increase virus spread.
Perhaps not surprisingly, the persistent activation of the NF-kB pathway maintained by certain viruses
contributes to oncogenic transformation
(2). In addition to the classic studies with the
avian REV-T retrovirus which contains the v-Rel oncoprotein and induces a rapid and fatal B-cell
lymphoma in young birds (4), several lines of evidence demonstrate that NF-kB family members contribute to human oncogenesis. Localization of NF-kB–encoding
genes at sites of chromosomal translocations and genomic rearrangements
in cancer, high levels of NF-kB activity in
many breast cancer cells, and constitutive nuclear NF-kB complexes in Hodgkin’s lymphoma cells all
support this view (2). Furthermore, as discussed below, viral oncogene products, including human T-cell leukemia virus type 1 (HTLV-1) Tax protein and
Epstein-Barr virus latent infection membrane protein 1 (EBV LMP1), each act by unique mechanisms to
disrupt NF-kB regulation and initiate viral
transformation.
It appears, however, that also several bacterial or parasitic intracellular infections
activate NF-kB pathway like described above for the
viral infections.
Searching Medline for NF-kB and several
intracellular ‘parasites’, that are all associated with chronic disease in humans and/or animals, certainly give a lot of hits
via the formula: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=NF-kappaB+AND+*
- exchange
the ‘*’ in the end for the pathogens, if the links below doesn’t work …
Vira:
Cytomegalovirus,
Human
papilloma virus, Human
immunodeficiency virus,
Human
T-lymfototrophic virus, Ebstein-Barr virus (mononucleosis), Hepatitis C virus,
Hepatitis B virus, Human
herpes virus, Coxsackievirus
Bacteria:
Borrelia,
Treponema (syphilis), Leptospira (rat bite fever), Chlamydia, Mycoplasma,
Mycobacteria (tuberculosis), Rickettsia,
Ehrlichia, Bartonella
Parasites:
The only intracellular
parasite I searched for, which is also known to be associated with chronic
persistent infection, that gave no hits at all, was Babesia.
I suppose it is because
Babesia hasn’t been investigated regarding NF-kB
activation yet, since above two piroplasmatic
'cousins' Malaria and Theileria does induce NF-kB, there is reason to suspect that Babesia also knows the
same trick.
I’ve certainly not searched
for all , just enough to give a the reader a hint ….
When trying to combat intracellular infections, one cytokine of major
importance is TNF, which induces apoptosis
(programmed cell death), which can be inhibited by activation of NF-kB:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=NF-kappaB+AND+apoptosis
There are so many articles on
this interesting subject, but I can only mention a few on selected tickborne infections and similar, with are the
infections of special interest to me:
NF-kB-dependent
inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii
infection
Clifton DR et al. Proc Natl Acad Sci
U S A 1998 Apr 14;95(8):4646-51 PMID: 9539792 PDF [& PMID: 12819104 PDF]
The possibility that bacteria may have evolved
strategies to overcome host cell apoptosis was explored by using Rickettsia rickettsii, an obligate intracellular
Gram-negative bacteria that is the etiologic agent of Rocky Mountain
spotted fever. The vascular endothelial cell, the
primary target cell during in vivo infection, exhibits no evidence of apoptosis
during natural infection and is maintained for a sufficient time to allow
replication and cell-to-cell spread prior to eventual death due to necrotic
damage. Prior work in our laboratory demonstrated that R. rickettsii infection activates
the transcription factor NF-kappa B and alters expression of several genes
under its control. However, when R. rickettsii-induced
activation of NF-kappa B was inhibited, apoptosis of infected but not
uninfected endothelial cells rapidly ensued. In addition, human
embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit Ikappa B that rendered NF-kappa B inactivatable
also underwent apoptosis when infected, whereas infected wild-type human
embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell
apoptosis via a mechanism dependent on NF-kappa B activation. Apoptotic
nuclear changes correlated with presence of intracellular organisms and thus
this previously unrecognized proapoptotic signal,
masked by concomitant NF-kappa B activation, likely required intracellular
infection. Our studies demonstrate that a bacterial
organism can exert an antiapoptotic effect, thus
modulating the host cell's apoptotic response to its own advantage by
potentially allowing the host cell to remain as a site of infection.
Activation of human monocytic
cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional
activator NF-kappa B.
Norgard MV et al. Infect Immun 1996 Sep; 64(9): 3845-52 PMID: 10438943 PDF
There is increasing evidence that lipoproteins of Treponema pallidum and Borrelia
burgdorferi are key inflammatory mediators during syphilis and Lyme disease. A
principal objective of the present study was to identify more precisely
similarities and divergences among lipopolysaccharide
(LPS)- and lipoprotein-lipopeptide-induced
immune cell signaling events. Like LPS, purified
native B. burgdorferi OspA and synthetic analogs of
OspA, OspB, and two T. pallidum
lipoproteins (Tpp47 and Tpp17) all induced NF-kappa B translocation in THP-1
human monocytoid cells. Acylation
of OspA and the synthetic peptides was requisite for cell activation. Polymyxin B abrogated only the response to LPS. By using
70Z/3-derived pre-B-cell lines either lacking or expressing human CD14 (the LPS
receptor), it was observed that expression of human CD14 imparted
responsiveness to LPS but not to OspA or spirochetal lipopeptides (assessed by induction of NF-kappa B and
expression of surface immunoglobulin M). Finally, the biological relevance of
the observation that T. pallidum lipoproteins-lipopeptides induce both NF-kappa B and cytokine production
in monocytes was supported by the ability of the
synthetic analogs to promote human immunodeficiency
virus replication in chronically infected U1 monocytoid
cells; these observations also suggest a potential mechanism whereby a
syphilitic chancre can serve as a cofactor for human immunodeficiency virus
transmission. The combined data lend additional support to the proposal
that spirochetal lipoproteins and LPS initiate monocyte activation via different cell surface events but
that the signaling pathways ultimately converge to
produce qualitatively similar cellular responses.
Borrelia burgdorferi activates nuclear factor-kappa B and is a
potent inducer of chemokine and adhesion molecule
gene expression in endothelial cells and fibroblasts.
Ebnet K, Brown KD, Siebenlist UK, Simon MM, Shaw S. J Immunol 1997 Apr 1; 158(7): 3285-92 PMID: 9120285
Lyme disease, caused by the tick-borne spirochete
Borrelia burgdorferi, is a systemic infection with preponderance for the skin,
joints, heart, and nervous system. Inflammatory lesions of target organs are
characterized by the presence of spirochetes and inflammatory leukocytes. We
have analyzed the potential of B. burgdorferi to induce gene expression of chemokines and adhesion molecules in human endothelial
cells, keratinocytes, and fibroblasts. We find
induction of the chemokines RANTES
(regulated upon activation, normal T cells expressed and secreted), monocyte chemoattractant protein-1,
IL-8, gro-alpha, IFN-inducible
protein-10, and mig (monokine
induced by gamma-IFN), and of the adhesion molecules
E-selectin, ICAM-1, and VCAM-
Cytokines involved in human septic shock--the model of
the Jarisch-Herxheimer reaction.
Free download:
Studies of the cytokine cascade in animal models of
infection and human experiments involving endotoxin
infusion have contributed fundamentally to understanding the role of cytokines
in human sepsis. The complexity of this cytokine cascade has been difficult to
unravel in clinical sepsis. However, the Jarisch-Herxheimer reaction has been
identified as a model of the cytokine cascade in human sepsis and has provided
an excellent model for experiments involving blocking agents. TNF blocking has been shown to be important for
protection in animal models of sepsis, but has been somewhat disappointing in
humans because adverse events have generally outweighed benefits.
Detection
of plasma tumor necrosis factor, interleukins 6, and
8 during the Jarisch-Herxheimer Reaction of relapsing fever.
Negussie Y et al. J Exp
Med 1992 May 1; 175(5): 1207-12 PMID: 1569394 PDF
The Jarisch-Herxheimer Reaction (J-HR) is a clinical
syndrome occurring soon after the first adequate dose of an antimicrobial drug
to treat infectious diseases such as Lyme disease, syphilis, and relapsing
fever. Previous attempts to
identify factors mediating this reaction, that may cause death, have been
unsuccessful. We conducted a prospective trial in Addis Ababa, Ethiopia on 17
patients treated with penicillin for proven louse-borne relapsing fever due to
Borrelia recurrentis to evaluate the association of
symptoms with plasma levels of tumor necrosis factor
(TNF), interleukins 6, and 8 (IL-6 and -8). 14 of the
17 (82%) patients experienced a typical J-HR consisting of rigors, a rise in
body temperature (1.06 +/- 0.2 degrees C) peaking at 2 h, leukopenia
(7.4 +/- 0.6 x 10(-3) cells/mm3) at 4 h, a slight decrease, and then rise of
mean arterial blood pressure. Spirochetes were cleared from blood in 5 +/- 1 h
after penicillin. There were no fatalities, but constitutional symptoms were
severe during J-HR. Plasma TNF, IL-6, and -8 were
raised in several patients on admission, but a seven-, six-, and fourfold
elevation of these plasma cytokine concentrations over admission levels was
detected, respectively, occurring in transient form coincidental with observed pathophysiological changes of J-HR. Elevated plasma
cytokine levels were not detected in the three patients who did not suffer
J-HR. We conclude that the severe pathophysiological
changes characterizing the J-HR occurring on penicillin treatment of
louse-borne relapsing fever are closely associated with transient elevation of
plasma TNF, IL-6, and -8 concentrations.
Prevention of
Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha [see comments]
Fekade D et al. N Engl
J Med 1996 Aug 1; 335(5): 311-5 PMID: 8663853 PDF
BACKGROUND: In patients with louse-borne relapsing
fever (Borrelia recurrentis infection), antimicrobial
treatment is often followed by sudden fever, rigors, and persistent
hypotension (Jarisch-Herxheimer reactions) that are associated with increases
in plasma concentrations of tumor necrosis factor
alpha (TNF-alpha), interleukin-6, and
interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha
(anti-TNF-alpha Fab) could
suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized,
double-blind, placebo-controlled trial in 49 patients with proven louse-borne
relapsing fever. Immediately before the intramuscular injection of penicillin,
the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control
solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha
Fab had Jarisch-Herxheimer reactions with rigors, as
compared with 26 of the 29 control patients (P = 0.006). The controls had
significantly greater mean maximal increases in temperature (1.5 vs. 0.8
degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and
systolic blood pressure (25 vs.
Suppression
of acute Ixodes scapularis-induced
Borrelia burgdorferi infection using tumor necrosis
factor-alpha, interleukin-2, and interferon-gamma.
Zeidner N et al. J Infect Dis
1996 Jan; 173(1): 187-95 PMID: 8537658
Down-regulation of mammalian cytokine production has
been demonstrated during tick feeding. To examine the hypothesis that reconstitution of
cytokines during tick feeding could facilitate immune containment of Borrelia burgdorferi,
the following experiments were done. C3H/HeJ mice were given cytokines for 10
days after Ixodes scapularis
attachment. At day 21, ear biopsies were analyzed for B. burgdorferi.
Polymerase chain reaction analysis indicated a protection rate of 95% in mice
receiving tumor necrosis factor (TNF)-alpha.
Mice that received interleukin (IL)-2 or interferon (IFN)-gamma
had infection rates of 30%-45% compared with 83% for untreated controls. No
correlation was noted between neutralizing antibody, reactivity by Western
blot, and subsequent protection. Culture of B. burgdorferi in
cytokine-conditioned media indicated that TNF-alpha, IFN-gamma, and IL-2 were not cytotoxic
for B. burgdorferi. These data suggest that cytokine-induced protection
from B. burgdorferi infection was immune-mediated and that cellular immunity
may be associated with protection from
Synergistic effects of
interleukin-1beta, interleukin-6, and tumor necrosis
factor-alpha: central monoamine, corticosterone, and behavioral variations.
Brebner K et al. Neuropsychopharmacology
2000 Jun;22(6):566-80 PMID: 10788757
The proinflammatory
cytokines interleukin-1beta (IL-1beta), IL-6, and tumor
necrosis factor-alpha (TNF-alpha) influence neuroendocrine activity, promote central neurotransmitter
alterations, and induce a constellation of symptoms collectively referred to as
sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological
disturbances in humans. In the present investigation, systemic IL-1beta and TNF-alpha dose-dependently and synergistically disrupted
consumption of a highly palatable food source (chocolate milk), possibly
reflecting anorexia or anhedonia engendered by the
treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1beta and TNF-alpha provoked variations of amine turnover in the
hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this
respect. Nevertheless, in view of the central amine variations induced by the
cytokines, it is suggested that immune activation may come to influence complex
behavioral processes, as well as affective state.
Role of T cells and cytokines
in fatal and resolving experimental babesiosis:
protection in TNFRp55-/- mice infected with the human Babesia WA1 parasite. Hemmer RM et al. J Parasitol 2000 Aug;86(4):736-42 PMID: 10958449
The
full discussion section from this reference is cited below, because the authors
give a thorough explanations for the role of TNF-a
and other cytokines (including a lot of references) - and this is possibly a
common pathogenetic 'pathway' for several (all?)
intracellular parasitic infections ?
DISCUSSION:
TNF-a is a pleiotropic cytokine that
appears to be an integral component of the immunologic defense
network. TNF-a seems to be
required for resistance to several intracellular facultative bacteria and
parasites, including Listeria monocytogenes
and Leishmania major (Havell,
1989; Green et al., 191990; Kaufmann, 1993). In contrast, other evidence
demonstrates the detrimental effects of TNF-a on the
host. TNF-a is involved in
triggering the lethal effects of cachexia, septic
shock syndrome, inflammation, and other systemic manifestations of disease
(Tracey and Cerami, 1994). The fact that this
cytokine is crucial in organizing the events involved in both immunity and
disease demonstrates the complexity of TNF-a
function. Previous studies from this laboratory demonstrated that WA1 babesial infection results in pulmonary edema,
infiltration and adhesion of mononuclear cells to the pulmonary veins, and
endothelial cell activation, as demonstrated by hypertrophy and upregulation of intracellular adhesion molecule-1 (Hemmer
et al., 1999). There is much evidence that these inflammatory responses can
be mediated by TNF-a (Mulligan et al., 1993;
Urquhart, 1994; Luca et al., 1997). The effector
functions of TNF-a include
increased vascular permeability, upregulation of
adhesion molecule expression on endothelial cells, and stimulation of other
changes in vascular endothelium that contribute to tissue injury. Thus, the
pathology observed in WA1-infected mice correlates with known biological
effects of TNF-a and
suggests a role for its activity in the WA1-associated disease.
In the
present study we examined the difference in TNF-a
production by CD4+, CD8+, and gd+ splenic
T-cell subpopulations in fatal and resolving Babesia infections. Upregulation of TNF-a production
by gd+ T cells in fatal WA1 infections, but not in
resolving infections, suggested that TNF-a production
was detrimental to the host. Additional support for the role of TNF-a in the pathogenesis of WA1 came from infections of
TNFRp55-/- mice. These mice are resistant to either lipopolysaccharide
or bacterial superantigen-induced septic shock, a
syndrome mediated by TNF-a (Pfeffer
et al., 1993). Furthermore, in the characterization of TNFRp55-/- mice, it was
shown that inoculation of TNF-a triggered mononuclear
cell infiltration of lung, liver, and kidney in C57BL/6 mice, but not in
TNFRp55-/- mice (Neumann et al., 1996). This provides evidence that the TNFRp55
receptor is necessary for TNF-a mediated leukocyte
adhesion to activated endothelium. In our study, the TNFRp55-/- mice survived a
lethal WA1 infection, thus demonstrating that abolishing TNFRp55 function
eliminated an important pathogenic mechanism of the WA1 parasite. This result
suggests that during a WA1 infection, signaling
through TNFRp55 promotes the recruitment of leukocytes to the lungs, and the
outcome is activation of the vascular endothelium, pulmonary edema, respiratory distress, and death. Taken together,
these results implicate TNF-a as an essential
component of the WA1-associated pathology.
In
addition to TNF-a, other cytokines were involved in
Babesia infections. IFN-g, another proinflammatory cytokine, was shown to have significanfly higher peak expression by CD8+ T cells in
WA1-infected mice compared to mice infected with B. microti. IFN-g is the principal macrophage-activating cytokine and
central in the regulation of TNF-a (Rudin et al., 1997). There is evidence that IFN-g synergizes with TNF-a to enhance an inflammatory response (Tracey and Cerami, 1994). Upregulation of
both of these cytokines during the WA1 infection could account for the severity
of the WA1-associated disease.
In
resolving B. microti infections, increased production of both IL-10 and IL-4 by
gd+ T cells occurred as the parasite load was
decreasing. Thus. in B.
microti infections, increased expression of IL-10 and IL-4 was important for
resolution of the parasitemia.
One
striking observation was that gd+
T cells were the major cytokine-producing cells in both WA1 and B. microti
infections. gd+ T cells act as a first line of defense against a pathogen and response of gd+ T cells to antigen happens faster than that ab+ [?, hard to read on my copy] T cells (Boismenu and Havran, 1997). These
responses indicate that the cytokine profile of gd+ T cells
may regulate the functional activities of both innate and acquired immune
responses. Production of IFN-g by gd+ T cells
has been shown to prime macrophages for TNF-a
expression (Nishimura et al., 1995). Other studies of intracellular organisms
imply that control of pathogen dissemination and host tissue damage requires
the regulatory influence of gd+ T cells (Rosat et al., 1993; Fu et al.. 1994). These studies cast gd+
T cells as an important regulatory cell for both innate and acquired immune
responses. Despite the fact that gd+ T cells
were the predominant cytokine-producing cells detected in our experiments, gd-/- mice behaved similar to controls when they were
infected with either WA1 or B. microti. This result is not entirely surprising
in light of the fact that
gd+ T cells make up a small percentage
of all T cells, approximately 2-5% in the mouse spleen. Certainly other cell
types are major producers of cytokines. Macrophages and natural killer cells
that produce TNF-a and IFN-g, respectively, could contribute to the WA1-associated
pathology. The flow cytometry results showed limited
involvement of cytokine production by CD4+ and CD8+ T cells. This was probably
not due to technical difficulties, because IFN-g
production was observed in CD8+ T cells, and IL-2 expression was detected in
CD4+ T cells (data not shown). It is possible that the cytokine expression was
below the level of detection for this assay, or that cytokines other than the
ones we tested are involved in Babesia infections. It is important to note that
in this study, the T cells were not restimulated in
vitro, and this may explain the paucity of cytokine expression by CD4+ T cells.
Because it was well established that CD4+ and CD8+ T cells have many important
functions in defense against intracellular pathogens,
we used CD4-/- and CD8-/- mice to study the effects of an absence of these
T-cell subpopulations on the outcome of WA1 and B. microti infections. There
was a significant delay in parasite clearance in both WA1- and B.
microti-infected CD4-/- mice. A similar persistence in parasitemia
was observed in mice depleted of CD4+ T cells by monoclonal antibody treatment
(Shimada et al., 1996). These results demonstrate a role for CD4+ T cells in
the elimination of parasites from the blood. Following WA1 inoculation, CD8-/-
mice had a moderately increased survival rate. One possibility is that because
CD8+ T cells are a major source of lFN-g, the absenec of CD8+ T cells reduces the overall availabilty of IFN-g (Boehm et
al., 1997). Consequently, the synergistic effects of IFN-g
and TNF-a are inhibited, leading
to a reduced inflammatory response and increased survival. The protection in B.
microti-infected CD4-/- and CD8-/- mice suggests that either CD4+ or CD8+ T
cells, without the other subset present, but in the presence of B cells, gd+ T cells, and innate immune cells can be sufficient for
immunity. Our results emphasize the plasticity and redundancy of CD4+ and CD8+
T-cell functions in response to intracellular pathogens.
These
studies were undertaken to gain a more complete understanding of the role of T
cells and cytokines in the pathogenesis of WA1 infections and the resolution of
B. microti infections. We have shown that cytokine responses of splenic T cells were different during fatal and resolving
infections and that cytokines contribute to both host pathology and host
immunity. TNF-a activity
through TNFRp55 was essential to the WA1-associated disease. Additional studies
of T cells, B cells, endothelial cells, and innate immune responses are needed
to elucidate the different mechanisms involved in fatal and resolving Babesia
infections. Future experiments will be directed at studying the role of
cytokine-stimulated endothelial cells and macrophages in WA1 pathology.
In vitro
and in vivo induction of tumor necrosis factor alpha
by Borrelia burgdorferi.
Defosse DL, Johnson RC. Infect Immun
1992 Mar; 60(3): 1109-13. PMID: 1541526 PDF
Tumor necrosis factor alpha (TNF-alpha)
is an immunoregulatory cytokine with many biological
activities including the mediation of inflammation. We examined sera and
synovial fluids from patients seropositive for infection with Borrelia
burgdorferi using a radioimmunoassay specific for TNF-alpha.
Significant elevation of TNF-alpha was found in the
sera and synovial fluids of patients examined, while controls showed no
elevation. Sera of mice infected with B. burgdorferi contained elevated levels
of TNF-alpha which varied during the course of a
24-day infection. To determine whether B. burgdorferi is capable of inducing TNF-alpha production, spirochetes were added to adherent
human peripheral blood mononuclear cells or mouse peritoneal exudate cells and 24 h later supernatants were assayed. TNF-alpha induction occurred in a dose-dependent manner.
The maximum stimulation occurred when a ratio of 1 to 10 spirochetes per
mononuclear cell was used. At optimal concentrations, induction was not
diminished by inactivation of spirochetes or pretreatment
with polymyxin B. These results suggest that an
increase in TNF-alpha production may occur as a
result of infection with B. burgdorferi.
Microbial Lipopeptides Induce the Production of IL-
Infante-Duarte C, Horton HF. Byrne
MC, Kamradt T. J Immunol
2000 Dec 1;165(11):6107-6115. PMID: 11086043 PDF
Naive Th cells can be
directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4,
respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia
burgdorferi, the spirochaete that causes Lyme
disease, induces Th1 development in alphass TCR-transgenic Th cells. Here, we
used TCR-transgenic Th
cells and oligonucleotide arrays to analyze the
differences between Th1 cells induced by IL-12 vs
those induced by B. burgdorferi. Transgenic Th cells
primed with peptide in the presence of B. burgdorferi expressed several mRNAs,
including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric
single-cell analysis of Th cell cytokine production
revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine.
Instead, almost all IL-17-producing Th cells simultaneously
produced TNF-alpha and most IL-17(+) Th cells also produced GM-CSF.
This pattern was also observed in humans. Th
cells from synovial fluid of patients with Lyme arthritis coexpressed
IL-17 and TNF-alpha upon polyclonal stimulation. The
induction of IL-17 production in Th cells is not
restricted to B. burgdorferi. Priming of TCR-transgenic
Th cells in the presence of mycobacterial
lysates also induced IL-17/TNF-alpha coproduction. The physiological stimulus for IL-17
production was hitherto unknown. We show here for the first time that microbial
stimuli induce the expression of IL-17 together with TNF-alpha
in both murine and human T cells. Chronic IL-17
expression induced by microbes could be an important mediator of
infection-induced immunopathology.
Excerpts:
IL-12 is a dominant factor for Th1-induction both in
vitro (6, 7) and in vivo (24). Several microorganisms.
including Borrelia burgdorferi can induce IL-12
expression in macrophages (7, 25-29). ….
B. burgdorferi induces not only IL-12 but also other
cytokines in host macrophages, including IL-1b (29), TNF-a , IL-6 (30), and IL-10 (31). Whereas IL-1b and TNF-a can support Th1 phenotype development (27, 32,33), IL-6 and IL-10 would be considered antagonistic to Th1
induction (34,35). Therefore, the increased IFN-g
production and decreased IL-4 production induced by B. burgdorferi is the net
effect og diverse signals,
some of which antagonize each other. This complicated situation, rather than Th priming in the presence of selected polarizing cytokines
in vitro, is likely to be typical of differentiation in vivo induced by
microbial pathogens. …
Thus, IL-17, which has been found in inflammatory
lesions (38-41), is induced by microbial stimuli and coexpressed
with other proinflammatory cytokines. The failure to
down-regulate microbe-induced expression of IL-17 could therefore be one link
between infection and autoimmunity.
From ‘Results’:
Up-regulation of several cytokine and chemokine mRNA’s by B. burgdorferi or IL-12.
B. burgdorferi and synthetic lipopeptides
induce enhanced IL-17 production …. Thus, the presence of B. burgdorferi or the
synthetic lipopeptide derived from B. burgdorferi
OspA during T cell priming induced enhanced IL-17 production.
IL-17 is produced by activated CD4+, TCR-transgenic T cells.
IL-6 and IL-18 induce enhanced IL-17 production. …
Exposure to microbes such as B. burgdorferi or M. bovis
BCG strain Danish induces the production of multiple
cytokines in different host cells including APC.
IL-17 is coexpressed with TNF-a and GM-CSF,
but not with type 1 or 2 cytokines.
IL-17 does not exert an obvious effect on Th-phenotype development.
Coproduction of IL-17 and TNF-a by synovial fluid Th cells
from patients with Lyme arthritis and reactive arthritis. [Seven patients met established clinical and
serological criteria for the diagnosis of Lyme arthritis. Their clinical
characteristics have been described betore (47) One patient suffered from Chlamydia-associated acute
reactive arthritis.]
Discussion (all text included):
To date, the development, stability, and plasticity of
Th subsets have been studied mostly in T cells that
were cultured in vitro in the presence of cytokines and Abs (6, 8, 12, 13,
16-20). In addition, Th cells activated in vivo with
highly differentiated patterns of cytokine secretion have been isolated from
patients or in various models of chronic inflammatory diseases or in chronic
infection (14, 15, 23). Little is known about the
physiological pathways of Th differentiation and the
stability or plasticity of Th cytokine production
induced by microbes. Here, we used oligonucleotide
arrays to compare the effects of B. burgdorferi on the cytokine production of Th cells with the well-documented effects of exogenously
added IL-12 and anti-IL-4. This analysis revealed that a number of genes were
exclusively or predominantly induced by B. burgdorferi but not by IL-12. One
such gene was that for IL-17, which we decided to analyze in more detail.
IL-17 originally had been described as a cytokine
produced by activated murine cytotoxic
T cells and called CTLA-8 (48). Murine IL-17 is a
21-kDa glycoprotein consisting of 147 amino acids that has 57% sequence
identity with a herpesvirus Saimiri
protein (HVS 13, also called vIL-l7) (49). It shares
63% amino acid sequence homology with the 155-aa huIL-17 protein, but has no
obvious homologies with other cytokines (37, 50). Similar to other mRNAs
encoding proinflammatory cytokines, the human and murine IL-17 mRNAs possess several ATTTA
motifs (37, 48) associated with rapid mRNA decay (51,52).
A receptor for IL-l7 (IL-l7R) with ubiquitous tissue distribution has been
described. This IL-17R has no homology with any of the known cytokine receptor
families. Furthermore, there are no obvious motifs in the receptor's
intracellular domain, which would suggest how signal transduction is mediated
following ligation of the IL-l7R (36, 50). Similar
to TNF-a , with which it is coexpressed as described here, IL-17 activates the
transcription factors NF-k B and AP-1 (36, 50, 53, 54), both of which are
involved in the regulation of expression of proinflammatory
cytokines. Accordingly, IL-17 exhibits pleiotrophic
activities on various parenchymal cells. including the induction of IL-6. IL-8, G-CSF, leukemia inhibitory factor,
PGE2, ICAM-l. and matrix metalloproteinase
expression in fibroblasts and other stromal cells
(36, 37, 50, 55-57), production of NO, iNOS, and
cyclooxygenase-2 by chondrocytes (53, 58), induction
of osteoclast differentiation factor in osteoblasts (39), stimulation of granulopoiesis
(37, 59), maturation of dendritic cells (60), and costimulation of T cell proliferation (36). IL-17 mRNA had
been detected in activated murine T cells (36) and
human CD4 memory cells (37, 39, 50). Nothing is known
about its regulation or the stimuli that naturally induce IL-17 production.
Here, we show that IL-17 production by activated Th
cells is enhanced 6-fold by microbial lipopeptides.
Microbial lipopeptides did
not enhance the IL-17 production of T cells primed with plate-bound Abs against
CD3 and CD28 in the absence of APC [antigen
presenting cell]. Therefore, the microbial lipopeptides
act on APC rather than directly on T cells. Bacterial (lipo) proteins, such as OspA
or the mycobacterial 19-kDa protein. activate APC after binding to
Toll-like receptors (61, 62). Our findings that both spirochaetal
lipopeptides and mycobacterial
lysates induce IL-17 production in Th cells in an APC-dependent
manner are compatible with the hypothesis that Toll-like receptor-mediated
activation induces APC to produce a currently
unidentified factor(s) that induces IL-17 production in Th
cells. In support of this hypothesis, we found that exposure to IL-6 or IL-18,
two cytokines which are produced by activated APC,
also increased the IL-17 production of activated Th
cells. The fact that exogenously added IL-6 erihanced
IL-17 production of Th cells is of interest because
one of the major in vivo effects of IL-17 is the induction of IL-6, e.g., in
rheumatoid synovial cells (36, 37, 50, 55, 56). Furthermore, both TNF-a and IFN-g
have additive effects on the IL-17-induced expression of IL-6 (37). The IL-17
mRNA is equipped with eight ATTTA motifs (37, 48),
which should normally prevent long-term effects of mirobe-induced
IL-17 (51, 52). Chronic infection., e.g.. with B. burgdorferi or Chlamydia trachomatis
(63), could maintain an IL-17-inducing stimulus. The reciprocal
induction/enhancement of IL-17 and IL-6 could then contribute to the
pathogenesis of chronic inflammatory diseases such as antibiotic-resistant Lyme
arthritis (42, 63). Thus, IL-17-producing Th cells
could become an important therapeutic target for the suppression of chronic
inflammation. The role of infections in the other chronic inflammatory
conditions in which IL-17 has been detected (38-40, 55, 64, 65) remains to be
determined.
There
is ample evidence for IL-17 as a mediator of inflammation in humans. Several
studies have detected IL-17-expressing human T cells in inflammatory lesions. Rheumatoid
arthritis is the best-characterized example: IL-17 is expressed,
secreted, and functional in rheumatoid synovia (38,
39, 55) but not in osteoarthritic
synovia (38, 39). CD45RO+CD4+ T lymphocytes are the
source of IL-
We show here for the first time that microbial stimuli
induce IL-17 production in murine CD4+ Th cells and that the percentage of IL-17 producing
synovial fluid T cells from patients with Lyme arthritis or Chlamydia-induced
reactive arthritis is significantly higher than in controls. IL-17 production
is induced by B. burgdorferi both in mice and in patients and may be of
importance for the chronic inflammatory conditions, e.g., antibiotic-resistant
arthritis, sometimes induced by infection with B. burgdorferi. The highly
coordinate expression of IL-17 with TNF-a , together with its presence and function in chronic
inflammatory lesions, argue for an important role of IL-
Our analyses of IL-l7 coexpression
with other cytokines revealed that it is neither a typical Th1 nor Th2
cytokine. Accordingly, the in vitro conditions that induce either Th1 or Th2
development had no effect on the frequencies of IL-17-producing Th cells or the amount of IL-17 secreted into the culture
supernatants. Vice versa, exogenously added IL-17 did neither affect Thl/Th2
phenotype differentiation nor did it induce IL-17 production. Thus, IL-17
cannot be classified as typical Th1 or Th2 cytokine. Similarly, when the
cytokine production of human T cell clones obtained from rheumatoid synovium (68) or from inflammatory skin lesions (64, 65)
had been examined, no correlation between IL-17 production and the production
of either IL-4 or IFN-g (68) bad been detected such
that human IL-17 had previously not been classified as Th1 or Th2 cytokine.
Instead, we here describe that almost all IL-17-producing Th
cells, murine and human, also produce TNF-a , a potent proinflammatory
cytokine that is an effective therapeutic target in chronic inflammatory
diseases, such as rheumatoid arthritis (69) and chronic inflammatory bowel
disease (70). In both murine and
human Th cells. IL-17 production was also
positively correlated with that of another proinflammatory
cytokine, GM-CSF.
In summary, we have shown that microbial lipopeptides induce the production of IL-17 together with TNF-a and GM-CSF.
We demonstrated T cells coexpressing IL-17 and TNF-a in the synovial fluid of patients with Lyme arthritis
and suggest microbe-induced IL-17 expression as a possible mediator of
infection-induced immunopathology.
The pattern and level of
cytokines secreted by Th1 and Th2 lymphocytes of syphilitic patients correlate
to the progression of the disease.
Podwinska J, Lusiak M, Zaba R, Bowszyc J. FEMS Immunol Med Microbiol 2000 May;28(1):1-14. PMID: 10767602
The
results of our previous work indicated that cell-mediated immune response, of
importance in protection against Treponema pallidum, is distinctly inhibited at certain periods of
syphilitic infection. Considering that cytokines, produced by Th1 lymphocytes,
take part in this response and that their secretion may be regulated by
cytokines of Th2 lymphocytes, we examined if, and in which stages of syphilis,
such a regulation may exist. In this study we have examined the ability of
cells to produce IL-2, IFN and TNF
(Th1 or Th1 like cytokines) as well as IL-6 and IL-10 (Th2 or Th2 like
cytokines). It was found that cells of syphilitic patients were able to produce
IL-2, IFN, TNF, IL-10 and
weakly IL-6 already in primary seronegative syphilis.
At the same stage of syphilis, but seropositive, ability of Th1 lymphocytes to
produce cytokines reached the highest values, whereas the cells producing IL-10
lost this ability. The cells producing IL-6 and MIF
had the highest ability in secondary early syphilis. In this stage of syphilis
again slightly increased the ability of cells to secrete IL-10, which reached
the highest value in early latent syphilis. The growing ability to produce IL-6
and IL-10 was accompanied with a diminished production of IL-2, IFN and TNF nearly in all stages
of syphilis. Only MIF, in contrast to other
cytokines, was produced in late syphilis without distinct changes. The greatest
suppression of Th1 lymphocytes to produce cytokines and cells to secretion of MIF was found in early latent syphilis when the level of
IL-
Treatment of psoriatic
arthritis with antitumour necrosis factor-alpha
antibody clears skin lesions of psoriasis resistant to treatment with methotrexate.
Ogilvie AL et al. Br J Dermatol.
2001 Mar;144(3):587-9. PMID:
11260020
BACKGROUND:
In inflamed skin, keratinocytes and inflammatory
cells both produce large amounts of tumour necrosis factor (TNF)
-alpha, a cytokine with broad effects that are relevant to inflammation.
Blockade of this proinflammatory cytokine by a
monoclonal anti-TNF-alpha antibody might be
effectively used in the treatment of inflammatory skin diseases. OBJECTIVES: To
gather information about the efficacy of an anti-TNF-alpha
antibody (infliximab) in the treatment of skin
lesions of psoriatic arthritis. METHODS: Six patients with progressive joint
disease and psoriatic skin lesions unresponsive to methotrexate
therapy were treated with anti-TNF-alpha antibody.
The Psoriasis Area and Severity Index was determined before and 10 weeks after
initiation of therapy. RESULTS: Improvement of psoriatic skin lesions was
observed in all patients. In addition, a marked improvement of the joint disease
was noted. CONCLUSIONS: Therapy with anti-TNF-alpha
antibody may be an effective treatment regimen for both psoriatic arthritis and
psoriatic skin lesions.
Tumor necrosis factor-alpha (TNF
alpha) in cerebrospinal fluid from patients with meningitis of different etiologies: high levels of TNF
alpha indicate bacterial meningitis.
Glimaker M et al. J Infect Dis
1993 Apr; 167(4): 882-9. PMID: 8450254
The levels of tumor necrosis
factor (TNF)-alpha in cerebrospinal fluid (CSF) were analyzed in 139 patients with meningitis and in
20 control subjects. Elevated concentrations were observed in 42 (82%) of 51
patients with purulent bacterial meningitis (18/24 Haemophilus
influenzae, 13/14 Streptococcus pneumoniae,
7/7 Neisseria meningitidis,
and 4/6 with other purulent bacterial etiology). In
contrast, elevated levels were found in only 5 of 78 individuals with
nonbacterial meningitis (2/8 with herpes simplex type 2, 3/3 with varicella-zoster virus). Thus, the positive and negative
predictive values were 0.89 for indicating a purulent
bacterial meningitis. Raised CSF TNF alpha levels were observed in 7 of 8 patients with
purulent bacterial meningitis in whom the routinely used parameters did not
unequivocally indicate the diagnosis. Moderately increased levels were seen
in 5 of 6 patients with Mycobacterium tuberculosis meningitis and in 1 of 4
cases of Borrelia burgdorferi. Thus, the present study indicates that
concentrations of TNF alpha in CSF
usually can discriminate between purulent bacterial and nonbacterial
meningitis. These findings may contribute diagnostic guidance with routinely
used CSF parameters.
Interestingly both arsenium and
selenium also interact with NF-kB and its respective
inhibitor – can that perhaps explain the since ancient times empirically
demonstrated effect of these – in higher dose very toxic minerals - is there a
need for giving these as nutrition supplements in
small doses in order to enhance immune function ?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=NF-kappaB+AND+Arsen*
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=NF-kappaB+AND+Selen*
Arsenic suppresses necrosis induced by selenite
in human leukemia HL-60 cells.
Zeng H. Biol Trace Elem Res 2001 Oct;83(1):1-15. PMID: 11693998
Selenium, an essential trace element
for humans, has been shown to have anticancer effects. Arsenic, a possibly
essential ultratrace element for humans, has been
used in the treatment of leukemia. Anticancer effects of selenium and arsenic have
been related to their ability to induce apoptosis. Because humans are
exposed to diverse trace elements simultaneously, it is important to learn
their interrelationship. In this study, we demonstrate that sodium selenite (Na2SeO3) causes
apoptosis at 3 microM and necrosis at high
concentrations (> 3 microM) in HL-60 cells.
Similarly, both sodium arsenite (NaAsO2) at 50 microM and sodium arsenate (Na2HAsO4) induce
apoptosis at 500 microM and necrosis at higher
concentrations (> 50 microM and > 500 microM, respectively) in HL-60 cells. Arsenite/arsenate, but not selenite,
enhances AP-1 DNA-binding activity. This
finding indicates different mechanisms through which apoptosis is induced by
these two elements. Interestingly, we observed that HL-60 cell necrosis induced by a high
concentration (> 3 microM) of selenite
was essentially inhibited by arsenic (50 microM of
NaAsO2 or 500 microM of Na2HAsO4), which resulted in
a net effect of apoptosis. Because AP-1 DNA-binding activity was not induced in
the presence of a combination of necrotic amount of selenite
and apoptotic amount of arsenite/arsenate, the
observed apoptosis apparently was through the mechanism used by selenite. Our
results suggest, for the first time, that the toxic necrotic effect of selenite can be neutralized by arsenite/arsenate
at the cellular level.
A previously commonly used ‘tonikum’ used in Denmark to treat ‘chronic fatigue’ after
infection used to contain a small doses of arsenic, which was removed when the
toxicity of arsenic was described, then the ‘tonikum’
lost its effect and went out of use probably because of it no longer had the
same beneficial effect ? (according to an old
pharmacist).
In animals arsenic was still used now and
then as late as in the 1970’ies, because it was known to be able to raise a
lame animal for a while, so it could be sold by the horse-trader as seemingly healthy and is still used sometimes in other
countries, for instance by Tarello (according to
veterinarians).
Until about 1950 – when penicillin arrived on the scene –
arsenic was commonly used for treating infections – including spirochetoses like syphilis (and borreliosis).
Arsenic was used for and had very good effect on a patient
described by Garin & Bujadoux.
Paralysie
par les Tiques. J Med Lyon 1922;71:765-767 – a
case which in retrospect expressed almost all the most characteristic
features of what is today called Lyme borreliosis
- Abbreviated case-story translated by M. Kroun from French – pardon me in advance for any
translation errors, my french could certainly be
better:
June 14, 1922: JMB, 58 years old, got a tickbite by
Ixodes hexagonus on his
left buttock. He knew the tick well from bites on his dog and sheep, and removed it
without damaging its head. Three
weeks later, he was hit by a very rapidly developing, painful disease, with
alarming stabbing pains.
After this,
irradiating pain developed in his left ischiadicus
and he consulted dr. HINGLAIS,
who saw a red
inflamed area on the left buttock, with the tickbite in its center, the size of a 5 Franc coin. It was red, warm,
painful and with palpable inguinal lymphglands on the
same side. Later the rash increased in size into a wide, confluent one, without
vesicles, which ultimately covered his left and right buttock, hypochondriac
area, lower part of truncus and left leg down to the
knee.
No fever. Urine normal. In the same area as the rash, the diseased
suffered from severe pain, including a belt around the thorax and in right
plexus brachialis area with irradiating pain down to
the elbow. He suffered
terribly, without any relief from 'antineurotique'
medicine and also morphica had no or only transient
effect.
In July and August,
i.e. during 2 1/2 month, he suffered tremendously.
On Sep. 19, he traveled by automobile to dr. GARIN, who noted the following:
Lungs and heart
normal. Puls 96. Temp. 37.5. Liver not palpable. Leftsided neck adenitis, as a chain
of small glands along m. sternocleidomestoideus, but
none in axillae, genitalia or inguinal regions.
Nervous systeme: paresis of right m. deltoideus
with atrophy, it was impossible for him to lift his arm, otherwise normal
movements. No objective sensory disturbances, but the patient describe 2 very painful spots at the
basis of thorax and belt-formed pain corresponding to the 2 lowest intercostal nerves, causing breathing difficulty. These
pains were alleviated after the first injection of novarsenobezol.
No
trophic disturbances on the lower extremities. Normal
tendon reflexes. Normal pupil-reaction.
The sick man is
very disturbed, having chills and being restless.
Oct. 3. Same
findings, but when asked to sit up, a slight positive Kernig.
Lumbarpuncture the same day
reveals, spinal fluid under pressure, glucose normal, increased albumin, 75 WBCs
mostly polymorphonuclear cells. No microbes, no
spirochetes visible. Wassermann reaction slightly positive.
Oct. 17. The
symptoms have improved and the patient is discharged, but he still have reduced movement in his right arm and atrophy of the deltoideus muscle and he still suffers some pains at the
basis of the thorax.
Treatment: from Sep.
26 - Oct. 16 he was given 4 injections of neo-billon, 0.10, 0.30, 0.45, 0.60 cgr. - the last three times
preceded by cyan Hg. (Mercury)
Notably the most severe pain was
relieved after the first injection of novarsenobenzol.
Seen in the outpatient
clinic on Oct. 30 and Nov. 8, where he does not suffer much, but still have
reduced movement of the right arm.
Authors discussion:
This case seem to be a case of
'tick paralysis'. The Wassermann reaction was slightly positive, but that is
sometimes the case in other tick-borne diseases like Rocky Mountain Spotted fever and relapsing fever. On the other hand, does
this man not have any sign of syphilis.
In experiments, HAWDEN, in
It is possible to
infect lambs and pheasants via a tickbite. The
illness shows about 6-7 days after the bite.
It is not possible
to reproduce the illness via injection of blood from a sick into an animal.
He did not find the
pathologic agent.
Regarding the etiology, the english
authors suspects that an infectious agent is transmitted by the tick, or a
toxin is being inoculated.
We also admit
voluntarily that it must be an agent ('virus') transported by the tick.
This hypothesis is
supported by the adminstration of novarsenobenzol
to our patient, that was very effective in alleviating
the severe pain.
Our observation
differs from others in the english
literature, that our patient had a rash after the tickbite,
and it also differs regarding the tick that was responsible for causing this
disease, in our case it was an Ixodes hexagonus tick.
We propose to
collect ticks from the patients village and try to
produce the illness in an animal via tickbite.
Arsenite
inhibit NF-kB activity by stable expression of a kinase mutated form of IKKb
(inhibitor of KappaB):
Opposite effect of NF-kB
and c-Jun-N-terminal kinase on p53-independent GADD45
induction by arsenite.
Chen F et al. J Biol
Chem 2001 Jan 9. PMID:
11150309 PDF
Cell cycle checkpoint, a major genomic surveillance
mechanism, is an important step in maintaining genomic stability and integrity
in response to environmental stresses. Using cells derived from human bronchial
epithelial cells, we demonstrate that NF-kB and
c-Jun-N-terminal kinase (JNK)
reciprocally regulated arsenic trioxide (arsenite)-induced,
p53 independent expression of GADD45 protein, a cell cycle checkpoint protein
that arrests cells at G2/M phase transition. Inhibition of NF-kB activation by stable expression of a kinase
mutated form of IKKb (IKKb-KM)
caused increased and prolonged induction of GADD45 by arsenite.
In contrast, the induction of GADD45 by arsenite was
transient and less potent in cells where the NF-kB
activation pathway was normal. Analysis of cell cycle profile by flow cytometry indicated that NF-kB
inhibition potentiates arsenite-induced
G2/M cell cycle arrest. Abrogation of JNK activation,
on the other hand, decreased GADD45 expression induced by arsenite,
suggesting a role for JNK activation in GADD45
induction. These results may indicate a molecular mechanism that NF-kB and JNK differentially
contribute to cell cycle regulation in response to arsenite.
Arsenic-interferon-alpha-triggered apoptosis in HTLV-I
transformed cells is associated with tax down-regulation and reversal of
NF-kappa B activation.
El-Sabban ME et
al. Blood. 2000 Oct 15;96(8):2849-55. PMID: 11023521 PDF
Human T-cell lymphotropic
virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a
malignancy of mature activated T cells resistant to conventional chemotherapy. The
viral transactivator protein Tax plays a critical
role in HTLV-I-induced transformation and apoptosis
resistance by inducing I kappa B-alpha degradation,
resulting in the activation of the NF-kappa Bpathway.
In these HTLV-I-transformed cells, arsenic trioxide
(As) and interferon (IFN)-alpha synergize to induce
cell cycle arrest and apoptosis. We demonstrate that cell death induction
is only partly dependent upon caspase activation and
is not associated with modulation of bcl-2, bax, or
p53 expression. However, combined As and IFN induce
the degradation of Tax, associated with an up-regulation of I kappa B-alpha
resulting in a sharp decrease in RelA DNA binding
nuclear factor (NF)-kappa B complexes because of the cytoplasmic
retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably
accounts for cell death induction through inactivation of the NF-kappa B
pathway. Such specific targeting of the viral oncoprotein
by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides
strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)
AIDS and the
"Selenium-CD4 T Cell Tailspin" The Geography of a Pandemic.
Foster HD .
Townsend Letter for Doctors & Patients - december
2000: 94-99
Abstract: AIDS involves slow but relentless
declines in serum selenium and CD4 T-cells, both of which are independent
predictors of mortality. This relationship between selenium and the immune system is
one of positive feedback, in which a decline in either of these two variables
causes further depression of the other. Termed the "selenium-CD4 T Cell
Tailspin" by the author, this feedback loop plays a crucial role in both
the diffusion of HIV-1 and the associated development of AIDS. Manipulating
this tailspin opens new avenues for both prevention and treatment.
Review not
finished ….
Marie Kroun
april 2003
……………………….
Journal of the International Society
for Orthomolecular Medicine
http://www.healthy.net/library/journals/ortho/index.html