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 the atopic/asthmatic sensitized state was examined in isolated rabbit tracheal smooth muscle (TSM) tissue and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. During half-maximal isometric contraction of the tissues with acetylcholine, relative to control TSM, the atopic sensitized TSM exhibited significant attenuation of both their maximal relaxation (P < 0.001) and sensitivity (i.e., -log dose producing 50% maximal relaxation) to isoproterenol and PGE(2) (P < 0.05), whereas the relaxation responses to direct stimulation of adenylate cyclase with forskolin were similar in both tissue groups. The impaired relaxation responses to isoproterenol and PGE(2) were ablated in sensitized TSM that were pretreated with either the IL-1 recombinant human receptor antagonist or an IL-1 beta-neutralizing antibody. Moreover, extended studies demonstrated that, in contrast to their respective controls, both passively sensitized rabbit TSM tissue and cultured cells exhibited markedly induced expression of IL-1 beta mRNA at 6 h after exposure to the sensitizing serum, a finding similar to that also obtained in passively sensitized human bronchial smooth muscle tissue. Finally, unlike their respective controls, passively sensitized TSM tissue and cultured cells also displayed progressively enhanced release of IL-1 beta protein into the culture media for up to 24 h after exposure to atopic/asthmatic serum. Collectively, these observations provide new evidence demonstrating that the altered responsiveness of atopic/asthmatic sensitized airway smooth muscle is largely attributed to its autologously induced expression and autocrine action of IL-1 beta.