Testis

Ischemia-Reperfusion of the Murine Testis Stimulates the Expression of Proinflammatory Cytokines and Activation of C-Jun N-Terminal Kinase in a Pathway to E-Selectin Expression

Abstract

Ischemia-reperfusion (IR) of the testis results in germ cell-specific apoptosis and can lead to spermatogenesis. Germ cell-specific apoptosis after IR of the testis has been shown to be correlated with and dependent upon neutrophil recruitment to the testis after IR. Studies employing E-selectin deficient mice have demonstrated that E-selectin expression is critical for neutrophil recruitment to subtunical venules in the testis after IR and for the resultant germ cell-specific apoptosis. The present study investigates the in vivo signaling pathway that exists after IR that leads to neutrophil recruitment in the murine testis. Mice were subjected to a 2 hr period of testicular ischemia followed by reperfusion. Results demonstrate that the proinflammatory cytokines, TNFand IL-1, are stimulated after IR as is the phosphorylation of JNK. The downstream transcription factors of JNK, ATF-2 and c-jun, are also phosphorylated at specific times after IR of the testis. Activation of the JNK stress-related kinase pathway, is correlated with an increase in E-selectin expression and neutrophil recruitment to the testis after IR. Intratesticular injection of IL-1 mimicked the effects on JNK and neutrophil recruitment seen after IR. These results suggest that testicular IR-injury stimulates IL-1 expression that leads to activation of the JNK signaling pathway ultimately leading to E-selectin expression and neutrophil recruitment to the testis. This provides the first evidence of a cytokine/stress-related kinase signaling pathway to E-selectin expression in vivo.