JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress.

Our previous studies have demonstrated that preconditioning with hydrogen peroxide (H(2)O(2)) activated the JAK-STAT pathway that played an important role in the cytoprotection, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mediated the late phase of cytoprotection induced by high concentration of H(2)O(2) after preconditioning. Here we sought to identify the downstream targets of the JAK-STAT axis that mediated H(2)O(2) preconditioning and the expression of iNOS and COX-2 in the early phase of H(2)O(2) preconditioning. It was shown that (1) Preconditioning with H(2)O(2) at 100 μmol/L for 90 min in PC12 cells induced significant expression of iNOS and COX-2. (2) Pretreatment with the iNOS inhibitor AG (10 μmol/L) or the COX-2 inhibitor NS-398 (10 μmol/L) respectively 20min before H(2)O(2) preconditioning not only inhibits the increased expression of iNOS or COX-2 but also abrogates the protective effects of H(2)O(2) preconditioning against apoptosis induced by oxidative stress. (3) Pretreatment with the JAK inhibitor AG-490 (10 μmol/L) 20 min before H(2)O(2) preconditioning obviously inhibits the up-regulation of iNOS or COX-2 induced by H(2)O(2) preconditioning. These results suggested that JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of H(2)O(2) preconditioning.