AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6.

Miles, Steven A.; Rezai, Ahmad; Salazar-Gonzalez, Jesus F.; Meyden, M Vander; Stevens, Ronald H.; Logan, Douglas M.; Mitsuyasu, Ronald T.; Taga, Tetsuya; Hirano, Toshio; Kishimoto, T

doi:10.1073/pnas.87.11.4068

Cited by 422 publications

(203 citation statements)

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“…The lesions also contain a variable inflammatory and mononuclear cell infiltrate. Studies published beginning in the late 1980s indicated that spindle cells derived from KS lesions could release, proliferate, and/or migrate in response to various growth factors that stimulate angiogenesis, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukins -1, -6 and -8, and platelet-derived growth factor (PDGF), and over-express receptors for multiple cytokines [19][20][21][22]. Activation of these receptors stimulates multiple pro-growth and anti-apoptotic pathways via PI3kinase/Akt/mTOR and extracellular receptor kinase (ERK) [23].…”

Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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“…6,7 Of particular interest are the findings that these cells secrete and respond to interleukin-6 (IL-6) and oncostatin M (OSM) suggesting a possible autocrine and/or paracrine growth regulation. 6,[8][9][10] HHV-8 infection may conceivably cause the cytokine production in these cells. 11 It is known that viral genes can transactivate cellular genes; such transactivation is thought to be one of the mechanisms of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines

et al. 1999

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. In addition, we tested the response of the PEL cells to selected cytokines and the effects of neutralizing anti-cytokine and anti-cytokine receptor antibodies. Using specific ELISAs, PEL cell lines were found to produce large amounts of interleukin-6 (IL-6; 10-5000 pg/ml), IL-6 soluble receptor (IL-6sR; 30-600 pg/ml), IL-10 (600-80 000 pg/ml) and oncostatin M (OSM; 50-80 pg/ml) which in most cases were significantly higher than the levels produced by the Burkitt, B-NHL or myeloma cell lines; on the contrary, PEL cell lines did not elaborate significant levels of macrophage inhibitory protein (MIP-1␣) and leukemia inhibitory factor (LIF). However, the levels of MIP-1␣ were increased 10-to 100-fold by treatment with phorbol ester TPA. PEL cell lines did not respond proliferatively to IL-6, IL-10, IL-11, LIF, MIP-1␣, or OSM. Incubation with IL-6sR and IL-6 inhibited cell growth. Anti-IL6 neutralizing antibodies had no effect on PEL cell line proliferation; conversely, whereas anti-IL6R alone inhibited only weakly, anti-gp130 and anti-gp130 plus anti-IL6R showed strong inhibitory effects (Ͼ20% inhibition in 5/9 lines and Ͼ60% inhibition in 3/9 lines). In summary, PEL cell lines produce high amounts of cytokines (IL-6, IL-10, OSM); proliferation could be inhibited by blocking the receptors of the IL-6 signaling pathway.

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“…Ftirihermore. IL-6 is known to be a growth factor lor multiple myeloma [36,37] and Kaposi's sarcoma [38,39] and-as a eonsequence of polyelonal B cell stimulalion-mighi be related to Ihc increased frequency of B cell malignancies in HIV-infected individuals [40|. Thus, differences in plasma IL-6 levels might result in a differenl risk of developing sueh malignancies.…”

Section: Discussionmentioning

confidence: 99%

Defective IL-6 secretion in HIV-infected haemophilia patients

Weimer

Zipperle

Daniel

et al. 1993

Clinical and Experimental Immunology

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SUMMARY To study the role of IL‐6 in HIV‐induced B cell defects, in vitro B cell responses and IL‐6 secretion were determined simultaneously in 67 haemophilia patients, Twenty‐three palients were HIV (Group 1). 27 HIV+ stage CDC II, III (Group 2). and 17 vi‐ere HIV4 stage CDC IV (Group 3). Pokeweed mitogen (PWM) was used forTeelI‐dependent and Staphylococcus aureus Cowan 1 (SAC I) for T cell‐independent B cell stimulalion. B cell differentiation was assessed in a reverse haemolytic plaque assay and by ELISA determination of IgG and IgM in culture supernatants. An ELISA was used to measure IL‐6 in plasma and culture supernatants, HIV+ patients showed impaired immunoglobulin‐secreting cell (ISC) responses after T cell‐independent and T cell‐dependent stimulation (P < 0·000l and P<0·01, respectively), whereas IL‐6 secretion. IgM and IgG responses were comparable to those in hcallhy controls. HIV+ patients at stage CDC II, Ml or IV demonst rated significantly reduced mitogen‐stimulated IL‐6 secretion (P < 0·05. PWM; P < 0·001. SAC lj as well as impaired ISC and IgG responses (P < 0·01. PWM; P≤ 0·0001, SAC I), CDC IV patients showed reduced IgM responses in addition (P < 0·02, PWM; P < 0·0005. SAC I). Plasma iL‐6 levels were elevated both in HIV* patients (CDC II. Ill patients: 165 ± 73 pg/ml. P < 0·005; CDC IV patients: 58 ± 18 pg/ml, P < 0·001) and in HIV patients (283 ± 65 pg/ ml. P<0·0001) which appeared to be a T cell effect induced by treatment with haemophilia factor concentrates. Our data provide evidence for different types of B cell deficiencies in HIV patients (impaired ISC response only) and HIV+ patients (impaired ISC as well as IL‐6 and IgM /lgG responses). The defective IL‐6 secretion in HIV+ patients is likely to affect terminal B cell differentiation and this may explain the reduced immunoglobulin secretion in these patients in response to antigenic challenge.

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AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6.

Cited by 422 publications

References 19 publications

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines

Defective IL-6 secretion in HIV-infected haemophilia patients

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