MUTUAL INHIBITION BY TGF-BETA AND IL-4 IN CULTURED HUMAN BRONCHIAL EPITHELIAL-CELLS

The airway epithelial cell may play a role as an effector cell, releas ing various cytokines and extracellular matrix components in immune re sponses, inflammation, and wound repair processes, thus contributing t o cytokine ''networks.'' The cytokines transforming growth factor (TGF )-beta and interleukin (IL)-4 are thought to have pivotal roles in air way diseases, with IL-4 having proinflammatory actions and TGF-beta ge nerally regarded to mediate repair and to attenuate immune responses. In asthma, where IL-4 and TGF-beta are thought to contribute to the in flammatory process and repair, respectively, interactions between thes e cytokines are likely to be of importance. Therefore, we studied the potential interaction of both cytokines by measuring IL-8 and fibronec tin release by cultured human bronchial epithelial cells (HBECs). IL-4 is capable of inducing IL-8 release from HBECs. This effect of IL-4 c an be blocked by the concurrent presence of the cytokine TGF-beta. In contrast, TGF-beta had a modest inconsistent stimulatory effect on IL- 8 release by itself and had no effect on the IL-8 release induced by t umor necrosis factor (TNF)-alpha. An antagonistic effect of IL-4 and T GF-beta was also observed on HBEC fibronectin release. TGF-beta stimul ated fibronectin release, and IL-4 was able to inhibit this. This effe ct was not due to a redistribution of fibronectin but appeared to be d ue to a true reduction in synthesis. Consistent with this, IL-4 and TG F-beta effects on IL-8 and fibronectin release were paralleled by chan ges in mRNA levels. The ability of TGF-beta to block IL-4-induced IL-8 release is certainly not the only mechanism to inhibit IL-8 release b ecause dexamethasone was capable of inhibiting both TNF-alpha- and IL- 4-induced release of IL-8. These results indicate that TGF-beta and IL -4 can have mutually inhibitory effects. The balance determined by thi s reciprocal inhibition may play an important role in regulating infla mmation repair and in diseases such as asthma.