title: Proteolytic cleavage confers nitric oxide synthase inducing activity upon prolactin.
abstract: Prolactin (PRL), originally associated with milk secretion, is now known to possess a wide variety of biological actions and diverse sites of production beyond the pituitary. Proteolytic cleavage is a common post-translational modification that can either activate precursor proteins or confer upon the peptide fragment unique biological actions not exerted by the parent molecule. Recent studies have demonstrated that the 16-kDa N-terminal proteolytic cleavage product of PRL (16K-PRL) acts as a potent inhibitor of angiogenesis. Despite previous demonstrations of 16K-PRL production in vivo, biological functions beyond its antiangiogenic actions remain unknown. Here we show that 16K-PRL, but not full-length PRL, acts to promote the expression of the inducible isoform of nitric oxide synthase (iNOS) and nitric oxide (*NO) production by pulmonary fibroblasts and alveolar type II cells with potency comparable with the proinflammatory cytokines interleukin-1beta, interferon gamma, and tumor necrosis factor alpha. The differential effect of 16K-PRL versus PRL occurs through a receptor distinct from known PRL receptors. Additionally, pulmonary fibroblasts express the PRL gene and endogenously produce 16K-PRL, suggesting that this pathway may serve both autocrine and paracrine roles in the regulation of *NO production. These results reveal that proteolytic cleavage of PRL confers upon this classical hormone potent iNOS inducing activity, suggesting its role in inflammatory/immune processes.
authors.affiliation: Centro de Neurobiologia, Universidad Nacional Autónoma de México, 76001 Querétaro, Qro, México.
authors.forename: A M
authors.initials: AM
authors.lastname: Corbacho
authors.forename: G
authors.initials: G
authors.lastname: Nava
authors.forename: J P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: G
authors.initials: G
authors.lastname: Noris
authors.forename: Y
authors.initials: Y
authors.lastname: Macotela
authors.forename: I
authors.initials: I
authors.lastname: Struman
authors.forename: G
authors.initials: G
authors.lastname: Martinez De La Escalera
authors.forename: B A
authors.initials: BA
authors.lastname: Freeman
authors.forename: C
authors.initials: C
authors.lastname: Clapp
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010446:Peptide Fragments; D009569:Nitric Oxide; D011388:Prolactin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat