Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 5, Issue 7-8, Pages 1299-1309Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2005.03.019
Keywords
asthma; STAT1; histamine; inverse agonism; PKA; crosstalk
Categories
Funding
- NIAID NIH HHS [2R15 AI032470-03A2] Funding Source: Medline
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Signal transducer and activator of transcription-1 (STAT1) is a latent signal transducer protein which, on phosphorylation, is translocated from the cytoplasm to the nucleus and is subsequently activated. This study was designed to determine the involvement of histamine receptors in histamine-mediated effect on STAT1 phosphorylation. It is known that the actions of histamine mediated through H1 and H2 receptors are dependent on their respective downstream pathways, Ca2+-PKC and cAMP-PKA. In this study, we investigated the significance of PKA in STAT1 phosphorylation. C57BL/6 mouse splenocytes were isolated and treated with histamine (10(-7)-10(-4) M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin. The phosphorylated STAT1 levels were analyzed by immunoblotting. Histamine receptor agonists amthamine and betahistine, histamine receptor antagonists pyrilamine maleate, tripelennamine, ranitidine, cimetidine and thioperamide, cAMP agonists N-6, 2'-0-dibutyryladenosine-3',5'-cyclic monophosphate sodium salt (db-cAMP) and forskolin, protein kinase A inhibitors N-(2-[p-bromocinnamylamino] ethyl)-5-isoquinoline-sulfonamide (H89) and Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate (RpcAMPs) and tyrosine kinase inhibitor tyrphostin were used to identify the upstream signal transduction pathways. We observed that histamine augmented the phosphorylation of STAT1 through both H1 and H2 receptors. Furthermore, H1 and H2 receptor antagonists displayed inverse agonism. Ca2+-PKC-induced phosphorylation of STAT1 was completely inhibited by H89 and significantly inhibited by RpcAMPs. DbcAMP and forskolin augmented the Ca2+-PKC-induced STAT1 phosphorylation thus suggesting a convergent crosstalk between the two histamine receptor signaling pathways, PKA and PKC. (C) 2005 Elsevier B.V All rights reserved.
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