Down regulation of interleukin-1β-induced nitric oxide production in lacrimal gland acinar cells by sex steroids

Purpose. Because the ocular surface is constantly exposed to allergens and irritants, it was reasoned that one cause of dry eye might be damage from inflammatory responses normally regulated by sex steroids. To test this hypothesis, we determined if sex steroids could down regulate nitric oxide (NO) production induced by interleukin-1beta (IL-1beta) in cultured rabbit lacrimal gland acinar cells. Methods. Cultured rabbit lacrimal gland acinar cells were exposed to IL-1beta to stimulate NO production. Stimulated cells were treated with different sex steroids and expression of iNOS protein determined by Western blotting and NO production by a nitrate/nitrite colorimetric assay. Results. It was found that the androgens testosterone, dihydrotestosterone, dehydroepiandrosterone and dehydroepiandrosterone-sulfate and 17beta-estradiol were able to inhibit interleukin-1beta-induced NO production in rabbit lacrimal gland acinar cells at physiological concentrations, while progesterone was not able to inhibit NO production. Sex steroid inhibition of NO production was not due to down regulation of iNOS protein production nor was it due to down regulation of GTP cyclohydrolase I with consequent loss of tetrahydrobiopterin production. Conclusions. The results reported here show that androgens and estrogens can down regulate cytokine-mediated responses in cells that are part of the ocular surface protection system and thereby may have an important role in regulating inflammatory responses in the eye. Deficiencies in these steroids, as occurs in postmenopausal women, may lead to damage of the cells responsible for producing the fluids that protect the ocular surface and subsequently to dry eye disease.