Proteolytic cleavage confers nitric oxide synthase inducing activity upon prolactin

Prolactin (PRL), originally associated with milk secretion, is now known to possess a wide variety of biological actions and diverse sites of producti on beyond the pituitary, Proteolytic cleavage is a common post-translationa l modification that can either activate precursor proteins or confer upon t he peptide fragment unique biological actions not exerted by the parent mol ecule. Recent studies have demonstrated that the 16-kDa N-terminal proteoly tic cleavage product of PRL (16K-PRL) acts as a potent inhibitor of angioge nesis. Despite previous demonstrations of 16K-PRL production in vivo, biolo gical functions beyond its antiangiogenic actions remain unknown. Here we s how that 16K-PRL, but not full-length PRL, acts to promote the expression o f the inducible isoform of nitric oxide synthase (iNOS) and nitric oxide (( NO)-N-.) production by pulmonary fibroblasts and alveolar type II cells wit h potency comparable with the proinflammatory cytokines interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha. The differential effect of 16K-PRL versus PRL occurs through a receptor distinct from known PRL re ceptors. Additionally, pulmonary fibroblasts express the PRL gene and endog enously produce 16K-PRL, suggesting that this pathway may serve both autocr ine and paracrine roles in the regulation of (NO)-N-. production. These res ults reveal that proteolytic cleavage of PRL confers upon this classical ho rmone potent iNOS inducing activity, suggesting its role in inflammatory/im mune processes.