Autocrine signaling by IL-10 mediates altered responsiveness of atopic sensitized airway smooth muscle

To elucidate the role and mechanism of action of interleukin (IL)-10 in reg ulating airway smooth muscle (ASM) responsiveness in the atopic asthmatic s tate, isolated rabbit tracheal ASM segments were passively sensitized with serum from atopic asthmatic patients or nonatopic nonasthmatic (control) su bjects in both the absence and presence of an anti-IL-10 receptor blocking antibody (Ab). Relative to control ASM, atopic asthmatic serum-sensitized t issues exhibited enhanced isometric constrictor responses to administered a cetylcholine and attenuated the relaxation responses to isoproterenol. Thes e proasthmatic effects were prevented in atopic asthmatic serum-sensitized ASM that was pretreated with anti-IL-10 receptor Ab. In complementary exper iments, exposure of cultured human ASM cells to atopic asthmatic serum indu ced upregulated expression of IL-10 mRNA. Moreover, extended studies demons trated that 1) exogenous IL-10 administration to naive ASM elicited augment ed contractility to acetylcholine and impaired relaxation to isoproterenol, 2) these effects of IL-10 were prevented by pretreating the tissues with a n IL-5 receptor Ab, and 3) IL-10 administration induced upregulated mRNA ex pression and release of IL-5 protein from cultured ASM cells. Collectively, these findings provide new evidence demonstrating that the altered respons iveness of atopic asthmatic serum-sensitized ASM is largely attributed to a ctivation of an intrinsic T helper type 2-type autocrine mechanism involvin g IL-10-mediated release and the action of IL-5 in the sensitized ASM itsel f.