Regulation of STAT6 and STAT4 Phosphorlation by Histamine

Signal transducer and activators of transcription (STAT) - 6 and STAT4 are the transcriptional factors crucial for the T helper cell differentiation into Thl and Th2 respectively. STAT6 is activated in response to IL-4 and IL-13 whereas IL-12 activates STAT4. The activation of these STAT factors is an important step in the modulation of T lymphocytes balance. Histamine alters the Thl/Th2 cytokine balance towards the Th2 cytokine profile and consequently plays a significant role in allergic diseases and asthma. This study was designed to investigate the effects of histamine on the phosphorylation of STAT6 and STAT4. C57BL/6 splenocytes were pre-treated with histamine followed by stimulation with PMA plus ionomycin and/or IL-12 and IL-4. The levels of phosphorylation and unphosphorylated STAT6 and STAT4 were assessed by immunoblot technique. Histamine caused upregulation of phosphorylation of STAT6 and STAT4 when stimulated with PMA + ionomycin. HI receptor antagonist pyrilamine reversed the effect of histamine on STAT6 and STAT4 phosphorylation. However, H2 receptor antagonist ranitidine and H3/H4 receptor antagonist thioperamide did not affect the histamine mediated hyper-phosphorylation of STAT6 and STAT4. Furthermore, HI receptor agonist betahistine enhanced the phosphorylation of STAT4 and STAT6 whereas H2 receptor agonist amthamine did not affect the phosphorylation of STAT4 and STAT6. Tyrosine kinase inhibitor, tyrphostin, inhibited the histamine mediated STAT6 phosphorylation whereas it did not affect the STAT4 phosphorylation. Histamine augmented the IL-4 induced phosphorylation of STAT6. The effects of histamine on the STAT6 phosphorylation were indirect since they were blocked both by the antibodies to IL-4 and IL-13 and in IL-4 knock out mice in the presence of IL-13 antibody. However, histamine did not affect the IL-12 induced phosphorylation of STAT4 which suggested that tyrosine kinase were not involved in this effect. These observations suggest that histamine indirectly affected the phosphorylation of STAT6 via its effect on the secretion of IL-4 and HI receptors played a role in this process. Histamine also mediated the upregulation of phosphorylation of STAT4 and HI receptors played a role in this effect.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2006

Author dc:creator

• Kharmate, Geetanjali

Advisor dc:contributor.advisor

• Khan, Manzoor M.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/55675

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/55675