THE MORPHOGENIC CYTOTOXIC AND PROSTAGLANDIN-STIMULATING ACTIVITIES OFINTERLEUKIN-1-BETA IN THE RAT OVARY ARE NITRIC-OXIDE INDEPENDENT/

Nitric oxide (NO) has been implicated as a mediator of physiologic and pathologic cellular injury. Since the cytokine interleukin-1 beta (IL -1 beta) induces nitric oxide synthase (NOS) activity as well as effec ts morphogenic/cytotoxic changes and increased prostaglandin (PGE(2)) levels in cultured whole ovarian dispersates, we set out to determine whether these actions are interrelated. Treatment with IL-1 beta resul ted in a marked increase in media nitrite and nitrate accumulation, mo rphological alterations, and increased release of lactate dehydrogenas e (LDH) into media. Addition of IL-1 receptor antagonist (RA) eliminat ed these IL-1 beta effects. In contrast, specific inhibitors of NOS fa iled to reverse IL-1 beta-induced morphogenic changes or LDH release i n spite of complete reduction of media nitrite to control levels. Simi larly, treatment with transforming growth factor beta(1), inhibited IL -1 beta-induced nitrite accumulation, but had no effect on the morphol ogic or cytotoxic endpoints. Moreover, the addition of sodium nitropru sside, an NO generator, resulted in progressive increments in media ni trite content without a corresponding increase in the IL-1 beta-associ ated morphogenic changes or media LDH content. Furthermore, IL-1-induc ed PGE(2) accumulation remained unaffected by specific NOS inhibition. These observations support the view that NO does not mediate the morp hogenic/cytotoxic or inflammatory-like (e.g., PGE(2) inducing) propert ies of IL-1 beta in cultured whole ovarian dispersates. Although the p recise role of NO in ovarian physiology remains unknown, it is possibl e that NO participates in the periovulatory modulation of ovarian bloo d flow by virtue of its potent vasodilatory activity.