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fact
sheet
Kaposi's Sarcoma and Interleukin-6
Thomas
Cherpes
Magee-Womens
Research Institute
University of Pittsburgh Medical Center
print
version
Published
May, 2002
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IL-6
Gene |
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Interleukin-6
(IL-6) is a pro-inflammatory cytokine that also has an important role in
immunity.
IL-6 induces growth and terminal differentiation of B cells;
secretion of immunoglobulins; differentiation and activation of T cells
and macrophages; and the induction of acute-phase response proteins (1).
The gene for IL-6 is located on chromosome 7p21 (2).
Many types of cells, including macrophages, T cells, fibroblasts,
and endothelial cells, produce IL-6 in response to stimuli such as
bacteria, viruses, and other cytokines, particularly IL-1 and tumor
necrosis factor, alpha (TNF).
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Gene Variants |
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The 5’ flanking region of the IL-6 gene is important in the
regulation of its expression. Recently, a G/C polymorphism was detected at position -174 of
the promoter region (3). This
same study found the frequency of the C allele in a group of 383
asymptomatic Caucasian men and women to be 0.403 (95% CI, 0.37-0.44) (3).
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Disease
Burden |
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In comparison with the G allele,
the C allelic variant has been associated with suppressed gene
transcription, and this polymorphic difference in IL-6 expression appears
to be clinically important. The
CC genotype is significantly underrepresented in persons with
systemic-onset juvenile chronic arthritis (OR=0.34 [95% CI, 0.12-0.98]) (3). Systemic-onset juvenile chronic arthritis is an
inflammatory disease whose signs and symptoms are the consequence of a
vigorous acute-phase reaction primarily mediated by IL-6.
On the other hand, the C allele has been associated with delayed
initial onset of the sporadic form of Alzheimer’s disease (OR=0.60 [95%
CI, 0.38-0.94]) (2). IL-6 has
increased central nervous system activity in patients with Alzheimer’s
disease, and an alteration of the immune response with C allelic
inheritance may retard onset of the disease.
The
importance of IL-6 in the pathogenesis of Kaposi’s sarcoma (KS) is
supported by substantial in vitro
evidence, including the observation that the cytokine stimulates KS
spindle-cell culture growth (4). In
a recent study that compared 115 HIV-infected men who had KS with a
control group of 126 deceased HIV-infected men who did not have KS, the CC
genotype, associated with decreased transcription of the
IL-6 gene, was seen significantly less often in
patients with KS than in controls (OR=0.35 [95% CI, 0.14-0.79]) (5). Furthermore, men
homozygous for the G allele, associated with increased production of IL-6,
were overrepresented among patients with KS (OR=2.11 [95% CI, 1.2-3.7]).
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Interactions |
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The etiology of KS is
complex, but infection with human herpesvirus 8 (HHV-8) appears to be the
primary and necessary event for development of the tumor (6). The sequence
of the HHV-8 genome suggests several ways the virus might promote
uncontrolled cellular proliferation.
The virus encodes for several genes, incorporated from its human
host, that are homologous to human oncoproteins, including a cyclin that
regulates the G1-to-S phase of the cell cycle, and a Bcl-2 like protein
that prevents apoptosis (6). In
addition, HHV-8 encodes for functional chemokines that may promote
angiogenesis and inhibit immune type I helper-T-cell responses.
Early in the development of a KS lesion, large numbers of
inflammatory cells are recruited to the site, and their production of
pro-inflammatory cytokines such as IL-6 and TNF-alpha are thought to
promote the angioproliferative inflammation that characterizes the
disease.
However,
HHV-8 infection alone is not sufficient for the development of KS, and
epidemiologic evidence supports the contribution of other environmental,
hormonal, and genetic cofactors in the pathogenesis of the condition. For
instance, co-infection with HIV dramatically increases the risk for
development of KS, as does the immunosuppressive therapy required by organ
transplant patients. Because KS is more prevalent in men than women, sex
hormones have also been postulated to act as cofactors in the pathogenesis
of the disease (7).
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Laboratory
Tests
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The
association between an IL-6 promoter polymorphism (G-174C),
increased IL-6 production, and subsequent increased risk for the
development of KS in HIV-infected men is a recent observation, and no
commercially available molecular diagnostic test exists to detect the
alleles. Serum levels of IL-6
can be measured reliably with a commercially available enzyme-linked
immunoassay (ELISA), but a nested case-control study found that
HIV-infected persons with increased IL-6 serum levels alone were not at
increased risk for KS (8). Serum
IL-6 levels may not accurately reflect IL-6 spindle-cell response in the
microenvironment of the lesion.
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Population
Testing |
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Detection
of the IL-6 gene G/C polymorphism in HIV infected populations may
prove clinically useful.
KS is the most common AIDS-associated cancer in the United States,
and persons identified to be at a particularly high risk for KS might be
offered prophylactic antiviral therapy to inhibit the replication of
HHV-8.
In
vitro susceptibility studies suggest that HHV-8 is resistant to
acyclovir and penciclovir but sensitive to ganciclovir and foscarnet (9).
Individuals considered to be at a lower risk for the development of KS
might be spared the potential toxicities associated with current antiviral
therapy.
High-risk persons may one day also be offered immune therapy
capable of decreasing the production of IL-6. Interestingly,
the case-control study outlined above that detected the association
between an IL-6 promoter polymorphism and the development of KS
also discerned a significant relation between the GG genotype and the
prevalence of HHV-8 infection (5). However, delineating the
relation between this genotype and susceptibility to the acquisition of
HHV-8 in HIV-infected men awaits the completion of prospective
investigations.
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References |
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- Paraskevas, F.
Cell Interactions in the Immune Response.
In Lee (ed.): Wintrobe’s
Clinical Hematology, 10th edition.
Philadelphia:Lippincott, Williams,
and Wilkins, 1999; 568-9.
- Papassotiropoulos
A, Bagli M, Jessen F, et al. A
genetic variation of the inflammatory
cytokine IL-6 delays the initial onset and reduces the risk for sporadic
Alzheimer’s disease. Ann
Neurol 1999; 45:666-8.
- Fishman
D, Faulds G, Jeffery R, et al. The
effect of novel polymorphisms in the IL-6
gene onIL-6 transcription and plasma IL-6 levels, and an association with
systemic-onset juvenile chronic arthritis.
J Clin Invest 1998; 102:1369-76.
- Samaniego
F, Markham P, Gallo R, et al. Inflammatory
cytokines induce AIDS-Kaposi’s sarcoma-derived spindle cells to produce
and release basic fibroblast growth factor and enhance Kaposi’s
sarcoma-like lesion formation in nude mice. J Immunol 1995;154:3582-92.
- Foster C, Lehrnbecher T, Samuels S, et al.
An IL-6 promoter polymorphism is
associated with a lifetime risk of development of Kaposi sarcoma in men
infected with human immunodeficiency virus.
Blood 2000; 96:2562-7.
- Antman K, Chang Y.
Kaposi’s sarcoma. N Engl J Med 2000; 342:1027-38.
- Klauke S, Schoefer H, Althoff P, et al.
Sex hormones as a cofactor in the pathogenesis of epidemic Kaposi’s
sarcoma. AIDS 1995; 9:1295-6.
-
Dourado I.
Interleukin 6 and AIDS-associated Kaposi’s sarcoma:
a nested case control study
within the Multicenter AIDS Cohort Study.
AIDS Res Hum
Retroviruses 1997;13:781-8.
-
Neyts
J, De Clerq E. Antiviral drug susceptibility of human herpes-virus 8.
Antimicrob Agents Chemother 1997;41:2754-6.
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Web sites |
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American Cancer Society
Kaposi’s
Sarcoma Support Group
National
Cancer Institute
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