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

• Published in: Biology of reproduction 2003-07, Vol.69 (1), p.202-210
• Main Authors: LYSIAK, Jeffrey J, NGUYEN, Quoc An T, KIRBY, Jennifer L, TURNER, Terry T
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 2; Animals; Biological and medical sciences; Cyclic AMP Response Element-Binding Protein - metabolism; Cytokines - genetics; Cytokines - metabolism; E-Selectin - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Gene Expression; Hormone metabolism and regulation; Inflammation Mediators - metabolism; Interleukin-1 - genetics; Interleukin-1 - metabolism; JNK Mitogen-Activated Protein Kinases; Male; Mammalian male genital system; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - metabolism; Neutrophils - immunology; Reperfusion Injury - enzymology; Reperfusion Injury - immunology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Testis - blood supply; Testis - injuries; Testis - physiopathology; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Vertebrates: reproduction
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.102.013318

Ischemia-reperfusion (IR) of the testis results in germ cell-specific apoptosis and can lead to aspermatogenesis. Germ cell-specific apoptosis after IR of the testis has been shown to be correlated with and dependent on neutrophil recruitment to the testis after IR. Studies that used 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-h period of testicular ischemia followed by reperfusion. Results demonstrate that the proinflammatory cytokines, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β), are stimulated after IR as is the phosphorylation of c-jun N-terminal kinase (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-1β also caused JNK phosphorylation and neutrophil recruitment to the testis. These results suggest that testicular IR injury stimulates IL-1β expression, which leads to activation of the JNK signaling pathway and ultimately 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.