GASTRIC ANTISECRETORY AND ANTIULCER ACTIONS OF IL-1 IN RAT INVOLVE DIFFERENT IL-1 RECEPTOR TYPES

Limited knowledge exists concerning the interleukin-1 (IL-1) receptor type (IL-1RT) mediating the potent antisecretory and gastroprotective actions of IL-1. In the present study, the gastric actions ofIL-1 beta and two related mutant proteins, yIL-1 beta Delta 4, an analogue that preferentially binds to IL-1-RTII, and mutant yIL-1 beta N7/Q, an analogue that has equal affinity as IL-1 beta for IL-1RTI and IL-1RTII, have been compared. Modulation of IL-1 gastric actions were also investigated using monoclonal antibody (MAb) preparations raised against IL-1RTI or IL-1RTII. In the pylorus-ligated rat, yIL-1 beta Delta 4, YIL-1 beta N7/Q, and IL-1 beta (all at 1 mu g/kg ip) reduced gastric acid secretion (50, 79, and 78%, respectively), indicating the importance of IL-IRTII binding for antisecretory activity. This was further substantiated in experiments using the MAb preparations, which showed that IL-1 beta (1 mu g/kg ip) antisecretory activity was reversed by MAb IL-1RTII (10-50 mu g/kg sc) but not by MAb IL-1RTI (50 mu g/kg sc). In contrast, at dosages 10-fold higher (10 mu g/kg ip) than that used in the study to inhibit acid secretion, IL-1 beta and yIL-1N7/Q equally reduced (similar to 80%) indomethacin-induced gastric damage, but yIL-1 beta Delta 4 was ineffective. The results using yIL-1 beta Delta 4 indicated that impairment of IL-1RTI binding capacity appeared to be paralleled by a decreased gastroprotective effect. Experiments using the IL-1 receptor antibody observed that MAb IL-1RTI (1,300 mu g/kg SC), but not MAb IL-1RTII (1,000 mu g/kg sc), reduced IL-1 beta (10 mu g/kg ip) protective actions against indomethacin-induced gastric damage. These data confirmed the likely participation of IL-1-RTI in mediating the gastroprotective actions of the cytokine. Taken together, these results demonstrate that IL-1-RTI and IL-1RTII mediate distinct gastric actions of IL-1 beta, IL-1-RTI for gastroprotective effects and IL-1-RTII for the antisecretory response of the cytokine. In addition, the study has provided further evidence that the gastroprotective actions of IL-1 beta are independent of its ability to reduce gastric acid secretion.