Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.
Unlike more well-studied large heat shock proteins (hsp) that induce both T cell antiinflammatory (IL-10, IL-4) and macrophage proinflammatory (TNF-alpha, IL-15, IL-12) cytokines, hsp27, a small hsp, has been primarily identified as a substrate of mitogen-activated protein kinase-activated protein kinase-2 involved in the p38 signaling pathway and activated during monocyte IL-10 production. Hsp27 can also act as an endogenous protein circulating in the serum of breast cancer patients and a protein whose induction correlates to protection from LPS shock. However, the cytokine-stimulating properties of hsp27 have been unexplored. In this study, exogenous hsp27 is demonstrated for the first time as a potent activator of human monocyte IL-10 production, but only a modest inducer of TNF-alpha. Although exogenous hsp27 stimulation activated all three monocyte mitogen-activated protein kinase pathways (extracellular signal-related kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38), only p38 activation was sustained and required for hsp27 induction of monocyte IL-10, while both ERK 1/2 and p38 activation were required for induction of TNF-alpha when using the p38 inhibitor SB203580 or the ERK inhibitor PD98059. Hsp27's transient activation of the c-Jun N-terminal kinase pathway, which can down-regulate IL-10, may contribute to its potent IL-10 induction. Hsp27's ERK 1/2 activation was also less sustained than activation by stimuli like LPS, possibly contributing to its modest TNF-alpha induction. The failure of either PD98059 or anti-TNF-alpha Ab to substantially inhibit IL-10 induction implied that hsp27 induces IL-10 via activation of p38 signaling independently of TNF-alpha activation and may be predominantly an antiinflammatory monokine stimulus.
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A K
AK
Department of Surgery, University of Massachusetts Medical School, Worcester 01655, USA.
Kodys
K M
KM
Yeh
B S
BS
Miller-Graziano
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C
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D002469:Cell Separation; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000276:immunology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D018832:Molecular Chaperones; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases