From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: New Kaposi's Sarcoma Study
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6706
Organization: unspecified
Date: Sat, 2 Jan 93 23:38:07 PST

        NEW STUDY ON THE PATHOGENESIS OF KAPOSI'S SARCOMA

Interesting new study by Barillari et al. concerning the possible 
pathogenesis of Kaposi's Sarcoma. In his study, he proposes that 
exogenous cytokines IL-1(alpha), IL-1(beta), Tumor Necrosis 
Factor(alpha), Tumor Necrosis Factor(beta), PDGF (Platelet Derived 
Growth Factor), and, to a lesser extent, IL-6 and GM-CSF, promoted the 
growth of AIDS-KS cells at concentrations shown to be biologically 
active in several systems. The addition of oncostatin M to the combined 
cytokines further increased the growth effect to the levels observed 
with the HTLV-II CM (conditioned media). 

Once again, treatment of HIV+ with corticosteroids is implicated in the 
the growth of AIDS-KS spindle cells.

Following the Barillari study are others providing more information on 
Oncostatin M.
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Barillari G, Buonaguro L, Fiorelli V, Hoffman J, Michaels F, Gallo RC, 
Ensoli B. Effects of cytokines from activated immune cells on vascular 
cell growth and HIV-1 gene expression. Journal of Immunology 
12/92;149(11):3727-3734.

Implications for AIDS-Kaposi's Sarcoma Pathogenesis 

Abstract: Kaposi's sarcoma (KS) arises more frequently in homosexual and 
bisexual men than in other groups of HIV-1 infected individuals. 
Clinico-epidemiologic date indicate that homosexuals often are infected 
with multiple microbial agents and/or subject to other antigenic 
stimuli, preceding or accompanying HIV-1 infection. Signs of immune 
activation, in fact, frequently have been detected in these individuals 
and the onset of KS can precede any sign of immunodeficiency. These data 
have suggested that products from activated immune cells may affect the 
development of AIDS-KS. Here we report that conditioned media from 
activated or dysregulated T cells contain a variety of cytokines that 
promote the growth of spindle cells derived from KS lesions of AIDS 
patients (AIDS-KS cells) and induce normal vascular cells, potential 
cell progenitors of the AIDS-KS cells, to acquire features of the KS 
cell phenotype ("spindle" cell morphology and growth responsiveness to 
the mitogenic effect of extracellular HIV-1 Tat protein). The same 
conditioned media or cytokines promote HIV-1 gene expression and rescue 
defective HIV-1 proviruses, interrupting HIV-1 latencyand increasing Tat 
production. The cellular and viral effects of cytokines are increased in 
an additive or synergistic manner by picomolar concentrations of 
extracellular Tat. These data suggest that cytokines produced by 
activated immune cells cooperate with HIV-1 infection in AIDS-KS 
pathogenesis.

Pages 3732-3733:
The immunodeficiency present in AIDS, coupled with the development of KS 
in immunosuppressed recipients of organ transplants, have suggested in 
the past that immunodeficiency is critical in KS pathogenesis. However, 
in two other forms of KS, classical Mediterranean and endemic-African, 
which are histologically identical to AIDS-KS, there does not appear to 
be significant immune deficiency. Release of cytokines may occur in 
response to the foreign tissue in organ transplant patients and, in 
addition, recent data from our laboratory have shown that 
corticosteroids, often used in the therapy of these patients, promote 
the growth of AIDS-KS spindle cells. It has been reported that 
homosexual and bisexual men often develop AIDS-KS prior to any immune 
deficiency and that they are more immune activated than other groups of 
HIV-1 infected individuals, who rarely develop KS. Multiple infectious 
agents, such as cytomegalovirus, human papilloma virus, amoeba, etc. are 
being associated withe the development of KS in homosexual and bisexual 
men. Immune activation and consequent cytokine production may represent 
the common pathway by which such different pathogens may participate in 
the development of KS in HIV-1 infected individuals. In addition, HIV-1 
infection itself can activate the expression of some of the cytokines 
normally produced after immune stimulation and T cell activation signals 
increase this effect. Our data may help to explain some of the biologic 
mechanisms underlying the high incidence of AIDS-KS in homosexual and 
bisexual men, and perhaps those few cases of low aggressive KS reported 
in HIV-1-negative homosexual men.
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Nair BC; DeVico AL; Nakamura S; Copeland TD; Chen Y; Patel A; O'Neil T; 
Oroszlan S; Gallo RC; Sarngadharan MG. Identification of a major growth 
factor for AIDS-Kaposi's sarcoma cells as oncostatin M. Science, 1992 
Mar 13, 255(5050):1430-2. 

Abstract: Conditioned medium from human T cell leukemia virus type 2 
(HTLV-II)-infected T cells supports the growth and long-term culture of 
cells derived from acquired immunodeficiency syndrome (AIDS)-associated 
Kaposi's sarcoma lesions (AIDS-KS cells). A protein of 30 kilodaltons 
was purified from conditioned medium that supports the growth of AIDS-KS 
cells. The amino-terminal sequence of this protein was identical to the 
amino-terminal sequence of Oncostatin M, a glycoprotein that inhibits 
the growth of a variety of cancer cells. Oncostatin M from conditioned 
medium stimulated a twofold increase in the growth of AIDS-KS cells at a 
concentration of less than 1 nanogram of the protein per milliliter of 
medium. 
========================================================================
Miles SA; Martinez-Maza O; Rezai A; Magpantay L; Kishimoto T; Nakamura 
S; Radka SF; Linsley PS. Oncostatin M as a potent mitogen for AIDS-  
Kaposi's sarcoma-derived cells. Science, 1992 Mar 13, 255(5050):1432-4.

Abstract: Oncostatin M, a cytokine produced by activated lymphoid cells, 
regulates the growth and differentiation of a number of tumor and normal 
cells. In contrast to its effects on normal endothelial and aortic 
smooth muscle cell cultures, Oncostatin M was a potent mitogen for cells 
derived from acquired immunodeficiency syndrome-related Kaposi's sarcoma 
(AIDS-KS). After exposure to Oncostatin M, AIDS-KS cells assumed a 
spindle morphology, had an increased ability to proliferate in soft 
agar, and secreted increased amounts of interleukin-6. Oncostatin M RNA 
and immunoreactive Oncostatin M protein were found in AIDS-KS-derived 
cell isolates. These results suggest that Oncostatin M may play a role 
in the pathogenesis of AIDS-KS. 
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Brown TJ; Rowe JM; Liu JW; Shoyab M. Regulation of IL-6 expression by 
oncostatin M. Journal of Immunology, 1991 Oct 1, 147(7):2175-80. 

Abstract: Endothelial cells produce immunomodulatory cytokines in 
response to soluble mediators of inflammatory/immune reactions. We have 
previously demonstrated that the leukocyte-derived cytokine, oncostatin 
M (Onco M) can alter endothelial cell morphology, regeneration, and 
fibrinolytic activity in vitro. Here we demonstrate that Onco M 
stimulates the production of the pleiotropic cytokine, IL-6, in cultured 
human endothelial cells (HEC) in a time- and dose-dependent manner. 
Specific antibodies to IL-6 neutralize the growth-inhibitory activity 
for human breast carcinoma cells that is secreted by HEC in response to 
Onco M treatment. Specific immunoassays indicate greater than 10-fold 
increases in the IL-6 content of culture supernatants as early as 6 h 
post-treatment with Onco M (ED50 = 17 pM). This stimulation of IL-6 
production by Onco M is associated with a sevenfold increase in 
intracellular levels of IL-6 mRNA. IL-1 alpha and TNF-alpha are also 
potent inducers of IL-6 production in these cells, the order of potency 
being IL-1 alpha greater than Onco M greater than TNF-alpha. TNF-alpha, 
but not IL-1 alpha, synergizes with Onco M to augment IL-6 production in 
HEC. HEC are 10 to 20 times more responsive to Onco M than are other 
nonendothelial cell types. In addition, HEC express 10 to 20 times 
greater numbers of high affinity cell-surface receptors for Onco M 
than do other nonendothelial cell types. Based on these findings, we 
propose that Onco M may represent a new immunomodulator regulating 
cytokine-induced gene products in endothelial cells. 
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Rose TM; Bruce AG. Oncostatin M is a member of a cytokine family that 
includes leukemia-inhibitory factor, granulocyte colony-stimulating 
factor, and interleukin 6. Proceedings of the National Academy of 
Sciences of the United States of America, 1991 Oct 1, 88(19):8641-5. 

Abstract: Oncostatin M (OSM), a glycoprotein of Mr approximately 28,000 
produced by activated monocyte and T-lymphocyte cell lines, was 
previously identified by its ability to inhibit the growth of cells from 
melanoma and other solid tumors. We have detected significant 
similarities in the primary amino acid sequences and predicted secondary 
structures of OSM, leukemia-inhibitory factor (LIF), granulocyte 
colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). Analysis of 
the genes encoding these proteins revealed a shared exon organization, 
suggesting evolutionary descent from a common ancestral gene. Using a 
panel of DNAs from somatic cell hybrids, we have shown that OSM, like 
LIF, is located on human chromosome 22. We have also demonstrated that 
OSM has the ability to inhibit the proliferation of murine M1 myeloid 
leukemic cells and can induce their differentiation into macrophage-like 
cells, a function shared by LIF, G-CSF, and IL-6. We propose that OSM, 
LIF, G-CSF, and IL-6 are structurally related members of a cytokine 
family that have in common the ability to modulate differentiation of a 
variety of cell types. 

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