UP-REGULATION OF CYTOKINE PRODUCTION IN ALVEOLAR MACROPHAGES BY HISTOGRANIN, A NOVEL ENDOGENOUS PENTADECAPEPTIDE

Recently, histogranin (HN), a newly found pentadecapeptide, was shown to enhance tumor necrosis factor (TNF) production by alveolar macrophages (AM). In this study, we have investigated whether HN was present in tissues rich with immune cells and further explored the effect of HN and [Ser(1)]HN on the production of TNF and other key cytokines. Relatively high levels of immunoreactive (ir)-HN were found in rat lung (14.9 pmol/g) and spleen (12.3 pmol/g), indicating its localization in close proximity to macrophages/monocytes and lymphocytes. Furthermore, HN and [Ser(1)]HN (10(-8)-10(-7) M) stimulated basal and lipopolysaccharide (LPS)induced interleukin 1 (IL-1) mRNA expression and IL-1 release from rat AM.[Ser(1)]HN also stimulated basal and LPS-induced interleukin-6 (IL-6) release. Although HN did not affect the kinetics of cytokine production, the maximal enhancing effect of HN was seen at 3 h for TNF, 6 h for IL-1 and 18 h for IL-6. These data indicate that HN can up-regulate a cytokine cascade involving TNF, IL-1 and IL-6 and suggest a role for this endogenous peptide in immune regulation.