Urocortin (Ucn), a new mammalian member of the CRF family, is a candidate endogenous ligand for type 2 CRF receptors. In a survey of peripheral tissues from adult male rats, we found that Ucn messenger RNA (mRNA) was abundant in the gastrointestinal tract and immune tissues such as thymus and spleen. We next tested the hypothesis that levels of Ucn mRNA levels in thymus and spleen would be altered after immune activation. As measured by ribonculease protection assay, lipopolysaccharide (LPS) induced a 2-fold time-dependent increase in thymic Ucn mRNA levels within 6 h. By contrast, splenic Ucn mRNA levels decreased after LPS. Because LPS activates the hypothalamus-pituitary-adrenal (HPA) axis, we examined whether the effects of LPS on Ucn mRNA might be mediated through changes in HPA axis hormones. Ucn mRNA in thymus, but not spleen, was significantly increased after ACTH injection; however, LPS did not increase Ucn expression in the thymus of adrenalectomized rats with corticosterone replacement, despite substantial increases in ACTH. Finally, sc injection of corticosterone stimulated Ucn mRNA comparably to that of LPS. Together, these results suggest that Ucn mRNA expression can increase after immune activation in a corticosterone-dependent manner, and that such changes in Ucn mRNA may be an additional consequence of HPA axis activation.