Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model
| Autor: | Rinpei Morita, Takashi Shichita, Eiichi Hasegawa, Hideyuki Yoshida, Akihiko Yoshimura, Fumie Konoeda, Go Muto, Yuki Sugiyama, Norihiro Suzuki |
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| Rok vydání: | 2010 |
| Předmět: |
Male
T-Lymphocytes T cell Biophysics Ischemia Interleukin-23 Biochemistry Brain Ischemia Brain ischemia Mice Piperidines medicine Animals Humans Pyrroles Molecular Biology business.industry Janus kinase 3 Interleukin-17 Antibodies Monoclonal Janus Kinase 3 Cell Biology medicine.disease Interleukin-12 Mice Inbred C57BL Disease Models Animal Pyrimidines medicine.anatomical_structure Immunology Cancer research Interleukin 12 Interleukin 17 Signal transduction business Janus kinase Immunologic Memory |
| Zdroj: | Biochemical and Biophysical Research Communications. 402:500-506 |
| ISSN: | 0006-291X |
| Popis: | Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke. |
| Databáze: | OpenAIRE |
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