SA Shore, J Laporte, IP Hall, E Hardy and RA Panettieri Jr
Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Decreased beta-adrenergic responsiveness is a characteristic feature of asthma. In order to determine whether cytokines released in the asthmatic airway contribute to this phenomenon, we measured changes in stiffness of cultured human airway smooth muscle (HASM) cells induced by isoproterenol (ISO) in control HASM cells and HASM cells pretreated with IL-1 beta (20 ng/ml for approximately 42 h). Stiffness was measured by magnetic twisting cytometry. HASM cells were obtained from normal tracheal tissue obtained at lung transplant, and studied in passages 4-7. In control cells, ISO caused a dose-related decrease in cell stiffness. IL-1 beta had no effect on baseline cell stiffness. However, IL-1 beta caused a rightward shift in the concentration- response curve to ISO and decreased the maximal effectiveness of this agonist. Decreased responses to ISO were also obtained with 2 ng/ml IL- 1 beta, or when cells were pretreated with IL-1 beta (20 ng/ml) for 22 h. This effect of IL-1 beta was not altered by pretreatment of the cells with pertussis toxin (100 ng/ml throughout the IL-1 beta exposure period). IL-1 beta also significantly attenuated the ability of prostaglandin E2 (PGE2) to decrease cell stiffness. In contrast, IL-1 beta had no effect on cell stiffness responses to dibutryl cAMP, a cell permeant analog of cAMP suggesting that the cytokine does not influence either the ability of cAMP to activate kinases, or the targets of these kinases which ultimately mediate cell relaxation. IL-1 beta (20 ng/ml for 40 h) caused a small (30%) but significant (P < 0.02) increase in basal cAMP, but also resulted in a 2-3-fold decrease in the changes in cAMP formation induced by either ISO or PGE2. In contrast, IL-1 beta had no effect on cAMP formation in response to forskolin, suggesting that IL-1 beta does not mediate its effects via changes in the expression or activity of adenylyl cyclase. Pretreatment with IL-1 beta had no significant effect on beta 2 adrenoceptor number assessed by [125I]-CYP binding in these cells, nor was there any significant effect of IL-1 beta on Gsa expression assessed by Western blot. In summary, our results indicate that IL-1 beta causes a concentration- and time- dependent decrease in responses of HASM cells to ISO and are consistent with the hypothesis that the effects of IL-1 beta are mediated by uncoupling of beta-receptors from Gs-induced activation of adenylyl cyclase.

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