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-al pha, IL-15, IL-12) cytokines, hsp27, a small hsp, has been primarily identi fied as a substrate of mitogen-activated protein kinase-activated protein k inase-2 involved in the p38 signaling pathway and activated during monocyte IL-10 production. Hsp27 can also act as an endogenous protein circulating its the serum of breast cancer patients and a protein whose induction corre lates to protection from LPS shock. However, the cytokine-stimulating prope rties of hsp27 have been unexplored, In this study, exogenous hsp27 is demo nstrated for the first time as a potent activator of human monocyte IL-10 p roduction, 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 k inase, and p38), only p38 activation was sustained and required for hsp27 i nduction of monocyte IL-10, while both ERK 1/2 and p38 activation were requ ired for induction of TNF-alpha when using the p38 inhibitor SB203580 or th e ERK inhibitor PD98059. Hsp27's transient activation of the c-Jun N-termin al kinase pathway, which can down-regulate IL-10, may contribute to its pot ent IL-10 induction. Hsp27's ERK 1/2 activation was also less sustained tha n activation by stimuli like LPS, possibly contributing to its modest TNF-a lpha induction. The failure of either PD98059 or anti-TNF-alpha Ab to subst antially inhibit IL-10 induction implied that hsp27 induces IL-10 via activ ation of p38 signaling independently of TNF-alpha activation and may be pre dominantly an antiinflammatory monokine stimulus.