Abstract
Members of the calcitonin peptide family—calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin2/intermedin (IMD)–exert modulatory effects upon monocytes and macrophages of various extrapulmonary origins. Utilizing the rat alveolar macrophage (AMφ) cell line NR8383, we here set out to determine to which extent these three peptides and their receptors are differentially regulated in AMφ and what specific effects they have on AMφ key functions. LPS treatment differentially up-regulated expression of the peptides and receptors. Among the three peptides, IMD mRNA content was lowest both in primary rat AMφ and NR8383 cells, whereas IMD peptide dominated in basal and LPS-stimulated secretion from NR8383 cells. Fcγ receptor-mediated phagocytosis and TNF-α production were inhibited by AM, IMD, and CGRP, whereas pro-IL-1β mRNA was slightly down-regulated exclusively by CGRP. Neither of these peptides affected IL-6 or IL-10 production. None increased intracellular calcium concentration, but AM significantly inhibited store-operated calcium entry. In conclusion, the rat AMφ cell line NR8383 is both a source and a target of the calcitonin peptide family members AM, IMD, and CGRP. Despite sharing proteins of the receptor complexes, AM, IMD, and CGRP each showed a characteristic pattern of effects and regulation, suggesting that these closely related peptides are not just redundant members of one common signaling pathway but act in concert by addressing parallel signaling cascades. Since peptide and receptor expression are up-regulated by LPS, these signaling pathways might act as inhibitory feedback mechanisms in pulmonary bacterial infection.
Highlights
Alveolar macrophages (AMφ) are phagocytes residing on the epithelial lining of airspaces
Messenger RNA expression of peptides and their receptor complex in NR8383 cells is regulated by LPS
IMD mRNA content was lowest both in rat AMφ and NR8383 cells, whereas IMD peptide dominated in basal, constitutive secretion from NR83838 cells, reaching more than 7 times higher levels compared to AM and 2.5 times higher levels compared to calcitonin gene-related peptide (CGRP)
Summary
Alveolar macrophages (AMφ) are phagocytes residing on the epithelial lining of airspaces. Activated AMφ are key players in orchestrating pulmonary inflammation by secreting various proinflammatory mediators, including tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-1β, IL8, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), proteinases, oxygen radicals, and peroxynitrite [4,5,6,7,8]. AMφ play an important role in resolution of inflammation by phagocytosing apoptotic neutrophils and secreting antiinflammatory agents, such as transforming growth factor beta (TGF-β1) and prostaglandin E2 (PGE2) [9,10]. Factors modulating AMφ function may have crucial influence upon maintenance of lung function under physiological and pathophysiological conditions
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