ABSTRACT
Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition to its principal role in immediate type hypersensitivity has been described to modulate IL-6 production and expression of IL-6 receptor. In this study, the IL-6 and IL-6 receptor expression was examined in histamine deficient histidine decarboxylase (HDC) knock-out mouse model. Our data suggest that in histamine deficient mice the inducibility of IL-6 is significantly reduced, whilst more IL-6 receptor/gp130 mRNA expresses in the liver than in wild type (HDC(+/+)) mice. These in vivo findings confirm earlier in vitro results and emphasize the efficacy of antihistamines in local IL-6 related processes.
Subject(s)
Gene Expression Regulation , Histamine/metabolism , Histidine Decarboxylase/deficiency , Interleukin-6/metabolism , Receptors, Interleukin-6/metabolism , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Cytokine Receptor gp130 , Gene Deletion , Gene Frequency , Histamine/genetics , Histidine Decarboxylase/genetics , Histidine Decarboxylase/metabolism , Interleukin-6/blood , Leukemia Inhibitory Factor Receptor alpha Subunit , Liver/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Mice, Knockout , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , Receptors, Interleukin-6/genetics , Receptors, OSM-LIFABSTRACT
The effect of histamine and histamine antagonists was examined on gene expression and biosynthesis of bacterial endotoxin (LPS) induced interferon gamma (IFNgamma) both in human peripheral mononuclear cells (PMBC) and in T-cell enriched fractions. We found, that histamine inhibited the LPS induced transcription of IFNgamma gene and biosynthesis of IFNgamma protein in PMBC and also in CD19-depleted cell populations. The inhibitory effect of histamine could be reversed by the H2 histamine receptor (HR2) antagonists cimetidine and ranitidine both in PMBC and in CD19-depleted cells, but not with triprolidine, an H1 receptor antagonist, suggesting that the inhibition of IFNgamma production is mediated through H2 receptors in these cell populations. In contrast to the inhibitory effect of histamine, cimetidine alone (in the absence of exogenous histamine) strongly stimulated both the IFNgamma mRNA and protein production, whereas this effect was hardly seen by and other H2 receptor blocker, ranitidine. This superinduction of IFNgamma gene by cimetidine disappeared if the CD19+ cells are removed from PMBC. These results suggest, that inhibition of IFNgamma gene expression by histamine is a direct effect of histamine on H2 receptor of T lymphocytes; however, the superinduction of IFNgamma by cimetidine requires the presence of other (probably primarily B) cell subsets.
