Adrenomedullin, a new peptidergic factor regulating inflammation and proliferation

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To elucidate the regulatory effects of adrenomedullin (AM) in the inflammation and proliferation, we investigated its effects on primary cultured rat skin fibroblasts and keratinocytes. AM suppressed proliferation of the fibroblasts in the presence of 1% fetal bovine serum and regulated the production of cytokines and growth factors in them. AM production in the fibroblasts was dynamically regulated by cytokines, hormones and inflammation-related reagents, while that in the keratinocytes remained unchanged by these substances. The receptors expressed on the fibroblasts were specific for AM, while those on the keratinocytes for calcitonin gene-related peptide (CGRP). Taken together, AM in the skin is deduced to regulate the vasodilation, proliferation, production of cytokines and growth factors mainly through the fibroblasts.By monitoring the cAMP production in LLC-PK_1 of a pig renal epithelial cell line, we screened new peptides in the acid extracts of pig brain. We found several candidates of unidentified bioactive peptides, and finally purified one peptide. By structural analysis, this peptide was verified to be a 38-residue peptide with a C-terminal amide and a disulfide linkage, and showed higher sequence homology to CGRP. This peptide reduced the plasma calcium concentration instead of the blood pressure, and stimulated the calcitonin (CT) receptor at the potency much higher than that of CT. Thus, we designated it as CT receptor-stimulating peptide (CRSP). The discovery of CRSP led us to recognize the complexity of the CT/CGRP superfamily that consists of CT, CGRP, AM, amylin and CRSP.