Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus
Document Type
Journal ArticlePublication Date
2000-10-18Keywords
Adjuvants, ImmunologicAnti-Inflammatory Agents,
Non-Steroidal
Cell Separation
Dose-Response Relationship, Immunologic
Enzyme Activation
*Heat-Shock Proteins
Humans
Interleukin-10
Lipopolysaccharides
Macrophage Activation
Mitogen-Activated Protein Kinases
Monocytes
Neoplasm Proteins
RNA, Messenger
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2000 Oct 1;165(7):3951-8.
DOI
10.4049/jimmunol.165.7.3951Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38258PubMed ID
11034403Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.165.7.3951
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