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Terminating the Stress: Peripheral Peptidolysis of Proopiomelanocortin-Derived Regulatory Hormones by the Dermal Microvascular Endothelial Cell Extracellular Peptidases Neprilysin and Angiotensin-Converting Enzyme

Ludwig-Boltzmann Institute of Cell Biology and Immunobiology of the Skin (T.E.S., M.F., M.B., T.A.L.) and Department of Dermatology (M.B., T.A.L.), Integrated Functional Genomics (S.K.), Interdisciplinary Center for Clinical Research, Medical Faculty, University of Münster, 48149 Münster, Germany

Address all correspondence and requests for reprints to: Thomas E. Scholzen, Ph.D., Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, Von-Esmarch-Strasse 58, 48149 Münster, Germany. E-mail: thoscho{at}uni-muenster.de.

The skin including the microvascular endothelium is an established peripheral source and target of the immunomodulatory proopiomelanocortin (POMC) peptides ACTH and -MSH. Whereas intracellular POMC peptide generation is well characterized, less is known on their extracellular processing in peripheral tissues by the neuropeptide-specific zinc metalloproteases neprilysin (NEP) and angiotensin-converting enzyme (ACE). This may locally control POMC peptide bioavailability and activation of ACTH/-MSH-specific melanocortin receptors (MCs). In a cell-free system, endothelial cell (EC) membranes prepared from ACE^high/NEP^low-expressing primary human dermal microvascular ECs and the ACE^low/NEP^high expressing EC line HMEC-1 degraded ACTH_1–39 over time, resulting in temporary increased -MSH immunoreactivity. Matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy peptide mapping and electrospray ionization-mass spectroscopy sequencing identified several stable fragments generated from ACTH_1–39, ACTH_1–24, and -MSH by EC membranes or recombinant NEP and ACE. Whereas some fragments could be assigned to a cell-specific NEP or ACE activity, other degradation products require additional enzyme activity. Pharmacological NEP inhibition enhanced the ACTH and -MSH-mediated activation of EC ectopically expressing MC₁. Likewise, selected peptides such as -MSH_2–12 generated from ACTH_1–39 and -MSH by recombinant NEP displayed equipotent MC₁-activating properties in vitro and antiinflammatory activity in murine allergic contact dermatitis in vivo as compared with the parental peptides. Thus, NEP and ACE significantly contribute to the EC processing of stress hormones (ACTH) and antiinflammatory peptides (-MSH), which modulates MC₁ activation but does not completely inactivate the peptide ligand. Because NEP and ACE are regulated by inflammatory mediators and UV light, this may be important for ACTH/MSH-modulated skin inflammation.