To elucidate the role of specific proinflammatory cytokines in regulating airway responsiveness, we examined the effects and mechanisms of action of IL-1 ␤ , TNF-␣ , and IL-2 on the ␤ -adrenoceptor-and postreceptor-coupled transmembrane signaling mechanisms regulating relaxation in isolated rabbit tracheal smooth muscle (TSM) segments. During half-maximal isometric contraction of the tissues with acetylcholine, relaxation responses to isoproterenol, PGE 2 , and forskolin were separately compared in control (untreated) TSM and tissues incubated for 18 h with IL-1 ␤ (10 ng/ml), TNF-␣ (100 ng/ml), or IL-2 (200 ng/ml). Relative to controls, IL-1 ␤ -and TNF-␣ -treated TSM, but not IL-2-treated tissues, depicted significant attenuation of their maximal relaxation and sensitivity (i.e., Ϫ log dose producing 50% maximal relaxation) to isoproterenol ( P Ͻ 0.001) and PGE 2 ( P Ͻ 0.05); whereas the relaxation responses to direct stimulation of adenylate cyclase with forskolin were similar in the control and cytokine-treated tissues. Further, the attenuated relaxation to isoproterenol and PGE 2 was ablated in the IL-1 ␤ -treated TSM that were pretreated with either the muscarinic M 2 -receptor antagonist, methoctramine (10

The role of IL-1 ␤ 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 Ͻ 0.001) and sensitivity (i.e., Ϫ log dose producing 50% maximal relaxation) to isoproterenol and PGE 2 ( P Ͻ 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 ␤ -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 ␤ 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 ␤ 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 ␤ . ( J. Clin. Invest. 1997. 99:117-124.)

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