Abstract
This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the mammalian testis and in two testicular pathologies, testicular torsion and orchitis. TNF alpha in the testis is produced by round spermatids, pachytene spermatocytes, and testicular macrophages. The type 1 TNF receptor has been found on Sertoli and Leydig cells and numerous studies suggest a paracrine mode of action for TNF alpha in the normal testis. IL-1 alpha has been reported to be produced by Sertoli cells, testicular macrophages, and possibly postmeiotic germ cells. IL-1 receptors have been reported on Sertoli cells, Leydig cells, testicular macrophages, and germ cells suggesting both autocrine and paracrine functions. While these proinflammatory cytokines have important roles in normal testicular homeostasis, an elevation of their expression can lead to testicular dysfunctions. Testicular torsion is a clinical pathology with results in testicular ischemia and surgical intervention is often required for reperfusion. A pivotal role for IL-1beta in the pathology of testicular torsion has been recently described whereby an increase in IL-1beta production after reperfusion of the testis is correlated with the activation of the stress-related kinase, c-jun N-terminal kinase, and ultimately resulting in neutrophil recruitment to the testis and germ cell apoptosis. In autoimmune orchitis, on the other hand, TNF alpha produced by T-lymphocytes and macrophages of the testis has been implicated in the development and progression of the disease. Thus, both proinflammatory cytokines, TNF alpha and IL-1, have significant roles in normal testicular functions as well as in certain testicular pathologies.
Highlights
The mammalian testis is an immunologically privileged site whereby tight junctions between Sertoli cells typically segregate germ cell autoantigens within the adluminal and luminal compartments of the seminiferous tubules [1]
At higher concentrations of tumor necrosis factor-α (TNFα), upregulation of membrane bound Fas was predominant and the germ cells were susceptible to Fas ligand (FasL)-mediated apoptosis. These results suggest that under physiologically low concentrations of TNFα the soluble form of Fas is produced by Sertoli cells and acts as a survival factor for germ cells; whereas, at high concentrations TNFα such as during inflammation TNFα induces membrane bound Fas which primes the Sertoli cells for FasL induced cell death [44]
Germ cell-specific apoptosis after IR of the testis is dependent upon the recruitment of neutrophils to the testis [5], and we have recently reported that an increase in proinflammatory cytokines after IR of the testis is correlated with activation of signaling pathways leading to neutrophil recruitment [22]
Summary
The mammalian testis is an immunologically privileged site whereby tight junctions between Sertoli cells typically segregate germ cell autoantigens within the adluminal and luminal compartments of the seminiferous tubules [1]. Recent data has demonstrated an increase in TNFα and IL-1β expression after reperfusion of the testis and that IL-1β may be responsible for stimulating a stress-related kinase signaling pathway leading to neutrophil recruitment from the testicular vasculature [22] Another testicular pathology is autoimmune orchitis which occurs in several species. E-selectin is an endothelial cell adhesion molecule responsible for the tethering and slow rolling of neutrophils to endothelial cells [82] These results suggest that an increase in TNFα and/or IL-1β after IR of the testis stimulates the activation JNK signaling pathway leading to the expression of Eselectin in endothelial cells and neutrophil recruitment (Figure 1). In biopsies of human testicular pathologies involving inflammation an increase in the number of macrophages and in TNFα expression by testicular macrophages has been observed adding further evidence for the involvement of TNFα in testicular inflammation [89]
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