AUTOCRINE ROLE OF INTERLEUKIN-1-BETA IN ALTERED RESPONSIVENESS OF ATOPIC ASTHMATIC SENSITIZED AIRWAY SMOOTH-MUSCLE

The role of IL-1 beta in regulating altered airway responsiveness in t he atopic/asthmatic sensitized state was examined in isolated rabbit t racheal smooth muscle (TSM) tissue and cultured cells passively sensit ized with sera from atopic asthmatic patients or nonatopic/nonasthmati c (control) subjects. During half-maximal isometric contraction of the tissues with acetylcholine, relative to control TSM, the atopic sensi tized TSM exhibited significant attenuation of both their maximal rela xation (P < 0.001) and sensitivity (i.e., -log dose producing 50% maxi mal relaxation) to isoproterenol and PGE(2) (P < 0.05), whereas the re laxation responses to direct stimulation of adenylate cyclase with for skolin were similar in both tissue groups. The impaired relaxation res ponses to isoproterenol and PGE(2) were ablated in sensitized TSM that were pretreated with either the IL-1 recombinant human receptor antag onist or an IL-1 beta-neutralizing antibody. Moreover, extended studie s demonstrated that, in contrast to their respective controls, both pa ssively sensitized rabbit TSM tissue and cultured cells exhibited mark edly induced expression of IL-1 beta mRNA at 6 h after exposure to the sensitizing serum, a finding similar to that also obtained in passive ly sensitized human bronchial smooth muscle tissue. Finally, unlike th eir respective controls, passively sensitized TSM tissue and cultured cells also displayed progressively enhanced release of IL-1 beta prote in into the culture media for up to 24 h after exposure to atopic/asth matic serum. Collectively, these observations provide new evidence dem onstrating that the altered responsiveness of atopic/asthmatic sensiti zed airway smooth muscle is largely attributed to its autologously ind uced expression and autocrine action of IL-1 beta.