Histamine enhances interleukin (IL)-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells.
The regulation of interleukin (IL)-6 synthesis by cAMP-increasing agents remains an unresolved issue. Since an increase in cAMP levels via activation of histamine H2 receptors does not induce IL-1 beta synthesis but enhances self-induction of IL-1 (Vannier, E., and Dinarello, C. A. (1993) J. Clin. Invest. 92, 281-287), we investigated whether histamine regulates IL-6 synthesis. Human peripheral blood mononuclear cells were stimulated with IL-1 alpha in the absence or presence of histamine (1 nM to 100 microM). IL-6 was measured using a specific radioimmunoassay. Histamine alone did not induce protein synthesis or mRNA accumulation for IL-6. Histamine (1-100 microM) enhanced IL-1 alpha-induced synthesis of IL-6 (p < 0.001). Cimetidine and ranitidine, H2 receptor antagonists structurally unrelated to each other, completely reversed the histamine-mediated increase in IL-1 alpha-induced IL-6 synthesis. However, diphenhydramine, an H1 receptor antagonist, did not reverse this effect. Prostaglandin E2, an activator of adenylate cyclase, also enhanced IL-1 alpha-induced synthesis of IL-6. Histamine increased and sustained steady-state levels of IL-6 mRNA in IL-1 alpha-stimulated cells, but reduced IL-6 mRNA half-life (3.5 h versus 1.8 h). Our results indicate that cAMP-increasing agents, such as histamine or prostaglandin E2, fail to induce IL-6 synthesis but rather enhance IL-1-induced IL-6 synthesis.
Vannier
E
E
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.
Dinarello
C A
CA
D000704:Analysis of Variance; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D012313:RNA / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis*; D011899:Ranitidine / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D011994:Recombinant Proteins; D012313:RNA; D002927:Cimetidine; D006632:Histamine; D011899:Ranitidine; D015232:Dinoprostone