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.
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 alpha (TNFalpha) and interleukin 1beta (IL-1beta), 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-1beta also caused JNK phosphorylation and neutrophil recruitment to the testis. These results suggest that testicular IR injury stimulates IL-1beta 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.
Lysiak
Jeffrey J
JJ
Department of Urology, University of Virginia Health Science System, Charlottesville, VA 22908, USA. jl6n@virginia.edu
Nguyen
Quoc An T
QA
Kirby
Jennifer L
JL
Turner
Terry T
TT
D051698:Activating Transcription Factor 2; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000276:immunology*; D015398:Signal Transduction; D013737:Testis / Q000098:blood supply / Q000293:injuries* / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D019040:E-Selectin; D018836:Inflammation Mediators; D007375:Interleukin-1; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases