Histamine Inhibits the Production of Interferon-induced Protein of 10 kDa in Human Squamous Cell Carcinoma and Melanoma

Abstract

Interferon-induced protein of (IP-10) inhibits tumor progression. Tumor cells can produce interferon-induced protein of IP-10 in response to interferon-g. Histamine in the vicinity of tumor cells may sustain the tumor progression. We examined the in vitro effects of histamine on interferon-induced protein of IP-10 production in human squamous cell carcinoma and melanoma. Histamine suppressed interferon-g-mediated interferon-induced protein of IP-10 secretion and mRNA expression in SV40-transformed keratinocytes, SCC15, SCC4, and melanoma WM115, WM266-4, and C32. Histamine suppressed interferon-g-induced interferon-mediated protein of IP-10 promoter activation in these cells, and the interferon-stimulated response element on the promoter was responsible for the suppression. Histamine suppressed interferon-g-mediated transcription through the interferon-stimulated response element and signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element. Histamine suppressed interferon-g-induced tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine-mediated suppression on the interferon-g-induced interferon-mediated protein of IP-10 synthesis was counteracted by the H2 receptor antagonist cimetidine, adenylate cyclase inhibitor SQ22536, and protein kinase A inhibitor H-89, but were not affected by H1 receptor antagonist mepyramine. Cimetidine, SQ22536, and H-89 also counteracted histamine-mediated suppression on the interferon-g-induced transcription through the interferon-stimulated response element, signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element, and tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine increased intracellular 3',5'-adenosine cyclic monophosphate level and protein kinase A activity in squamous cell carcinoma and melanoma, and the effects of histamine were blocked by cimetidine. These results suggest that histamine may interact with H2 receptor on squamous cell carcinoma and melanoma and generate 3',5'-adenosine cyclic monophosphate, which may activate protein kinase A. The cyclic 3',5'-adenosine monophosphate/protein kinase A signaling pathway induced by histamine may inhibit interferon-g-induced signal transducer and activator of transcription 1alpha activation and suppress interferon-induced protein of IP-10 synthesis.

Functional characterization of histamine receptor subtypes in a human bronchial epithelial cell line

“…Inhibition of IP-10 production was mediated solely by H 2 receptors. This is consistent with a previous study showing the involvement of H 2 receptors and cAMP in the regulation of IP-10 secretion (36). In contrast, modulation of MIG was also mediated by H 1 and H 3 histamine receptors whereas RANTES secretion was mediated by H 2 Studies on the possible role of CXCL9/MIG in inflammatory responses in the lung showed a strong association between MIG levels and the regulation of allergic airway inflammation.…”

H1 histamine receptor mediates inflammatory responses in human keratinocytes

“…This effect was mediated primarily by the H2 receptor and suggests that histamine may suppress antitumor immune responses. 26 We have also shown that levocetirizine very efficiently blocks all of the proinflammatory actions of histamine on keratinocytes. In contrast, the H2 antagonist cimetidine did not inhibit these inflammatory actions of histamine, as previously observed.…”

A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-α and Interferon-γ Inflammatory Effects in Human Endothelial Cells

“…TNF␣ induces IP10 secretion in mast cells but through NFkB and p38-MAPK pathways, not involving ERK, 21 whereas IFN␥-induced IP10 synthesis is suppressed by Stat1 inhibition. 22 The anti-inflammatory effects of PPAR␥ ligands, evaluated as the ability of TZD to inhibit IFN␥ proinflammatory effects, have been previously investigated in vasculopathies. 5 Although currently published studies suggest that the antiinflammatory action of TZD can be mediated both in vivo [23][24][25] and in vitro 9 by their ability to interfere with the transcriptional activity of NFB, the intracellular mechanisms underlying such effects might not be yet fully clarified.…”