| First Author | Huang W | Year | 2016 |
| Journal | J Allergy Clin Immunol | Volume | 137 |
| Issue | 4 | Pages | 1197-1205 |
| PubMed ID | 26581914 | Mgi Jnum | J:329775 |
| Mgi Id | MGI:6855877 | Doi | 10.1016/j.jaci.2015.08.056 |
| Citation | Huang W, et al. (2016) Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide. J Allergy Clin Immunol 137(4):1197-1205 |
| abstractText | BACKGROUND: Mast cells are indispensable for LPS-induced septic hypothermia, in which TNF-alpha plays an essential role to initiate septic responses. ITK and BTK regulate mast cell responses to allergens, but their roles in mast cell responses in LPS-induced sepsis are unclear. OBJECTIVE: We sought to investigate the roles of ITK and BTK in mast cell responses during LPS-induced septic inflammation. METHODS: Mice (genetically modified or bone marrow-derived mast cell-reconstituted Sash) were given LPS to induce septic hypothermia in the presence or absence of indicated inhibitors. Flow cytometry was used to determine LPS-induced cell influx and TNF-alpha production in peritoneal cells. Microarray was used for genomewide gene expression analysis on bone marrow-derived mast cells. Quantitative PCR and multiplex were used to determine transcribed and secreted proinflammatory cytokines. Microscopy and Western blotting were used to determine activation of signal transduction pathways. RESULTS: The absence of ITK and BTK leads to exacerbation of LPS-induced septic hypothermia and neutrophil influx. Itk(-/-)Btk(-/-) mast cells exhibit hyperactive preformed and LPS-induced TNF-alpha production, and lead to more severe LPS-induced septic hypothermia when reconstituted into mast cell-deficient Sash mice. LPS-induced nuclear factor kappa B, Akt, and p38 activation is enhanced in Itk(-/-)Btk(-/-) mast cells, and blockage of phosphatidylinositol-4,5-bisphosphate 3-kinase, Akt, or p38 downstream mitogen-activated protein kinase interacting serine/threonine kinase 1 activation significantly suppresses TNF-alpha hyperproduction and attenuates septic hypothermia. CONCLUSIONS: ITK and BTK regulate thermal homeostasis during septic response through mast cell function in mice. They share regulatory function downstream of Toll-like receptor 4/LPS in mast cells, through regulating the activation of canonical nuclear factor kappa B, phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt, and p38 signaling pathways. |
