Regulation of IL-6 expression by oncostatin M.
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.
Brown
T J
TJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Rowe
J M
JM
Liu
J W
JW
Shoyab
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008970:Molecular Weight; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D007375:Interleukin-1; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M