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The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis.

Lysiak JJ - Reprod. Biol. Endocrinol. (2004)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, University of Virginia, Charlottesville, VA 22908, USA. jl6n@virginia.edu

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.

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Following ischemia/reperfusion of the testis IL-1β expression is increased. Corresponding with the increase in IL-1β is an activation of JNK localized to endothelial cells in the testis. Two downstream transcription factors of JNK, ATF-2 and c-jun are also activated and are known to form a heterodimer and upregulate E-selectin expression. E-selectin expressed on the surface of endothelial cells aids in the recruitment of neutrophils to the testis. Once neutrophils are bound to endothelial cells they can transmigrate through the endothelial cells into the interstitium where they are poised to release factors such as reactive oxygen species or other cytokines. The source of IL-1β production after ischemia/reperfusion of the testis is currently unkown; however, Sertoli cells, Leydig cells, and interstitial macrophages are candidates.
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Figure 1: Following ischemia/reperfusion of the testis IL-1β expression is increased. Corresponding with the increase in IL-1β is an activation of JNK localized to endothelial cells in the testis. Two downstream transcription factors of JNK, ATF-2 and c-jun are also activated and are known to form a heterodimer and upregulate E-selectin expression. E-selectin expressed on the surface of endothelial cells aids in the recruitment of neutrophils to the testis. Once neutrophils are bound to endothelial cells they can transmigrate through the endothelial cells into the interstitium where they are poised to release factors such as reactive oxygen species or other cytokines. The source of IL-1β production after ischemia/reperfusion of the testis is currently unkown; however, Sertoli cells, Leydig cells, and interstitial macrophages are candidates.

Mentions: As early as 0.5 hr after IR of the murine testis an increase in the expression of both TNFα and IL-1β is observed [22] and this precedes the activation of JNK. JNK is a stress-related kinase that plays a critical role in the cellular response to many types of cellular stress. Two transcription factors downstream of JNK, ATF-2 and c-jun, are also activated, and immunolocalization of activated, phosphorylated, JNK (phospho-JNK) demonstrated immunoreactivity in intratesticular blood vessels [22]. Corresponding with this was an increase in E-selectin mRNA and protein 4 hr after IR of the testis [22]. Indeed, the E-selectin promoter is known to contain a positive regulatory domain II site which has been shown to bind a heterodimer of ATF-2 and c-jun [81]. 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 E-selectin in endothelial cells and ultimately neutrophil recruitment (Figure 1). In order to determine if TNFα, IL-1β, or both proinflammatory cytokines were eliciting this response, the cytokines were injected either alone or in combination to the testis and phosphorylation of JNK and neutrophil recruitment was examined. Results from these experiments revealed that injection of IL-1β mimicked the effects of IR on the testis, causing an activation of JNK and a recruitment of neutrophils to the testis [22]. Thus, an increase in IL-1β after IR of the testis stimulates an intracellular signaling cascade in testicular endothelial cells resulting in neutrophil recruitment and eventually germ cell death. The cell type responsible for the increase in IL-1β production after IR of the testis is currently unknown. Even though TNFα did not have a role in neutrophil recruitment or JNK activation in the testis, preliminary experiments in our lab suggest that the increase in TNFα may lead to the activation of NFκB in Sertoli cells (Lysiak and Turner, unpublished) and may influence germ cell apoptosis by increasing FasL expression in Sertoli cells. Identification of the mechanisms involved in germ cell-specific apoptosis after IR may lead to the development of therapies aimed at interrupting specific pathways in order to prevent the IR-induced loss of spermatogenesis.


The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis.

Lysiak JJ - Reprod. Biol. Endocrinol. (2004)

Following ischemia/reperfusion of the testis IL-1β expression is increased. Corresponding with the increase in IL-1β is an activation of JNK localized to endothelial cells in the testis. Two downstream transcription factors of JNK, ATF-2 and c-jun are also activated and are known to form a heterodimer and upregulate E-selectin expression. E-selectin expressed on the surface of endothelial cells aids in the recruitment of neutrophils to the testis. Once neutrophils are bound to endothelial cells they can transmigrate through the endothelial cells into the interstitium where they are poised to release factors such as reactive oxygen species or other cytokines. The source of IL-1β production after ischemia/reperfusion of the testis is currently unkown; however, Sertoli cells, Leydig cells, and interstitial macrophages are candidates.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC404472&req=5

Figure 1: Following ischemia/reperfusion of the testis IL-1β expression is increased. Corresponding with the increase in IL-1β is an activation of JNK localized to endothelial cells in the testis. Two downstream transcription factors of JNK, ATF-2 and c-jun are also activated and are known to form a heterodimer and upregulate E-selectin expression. E-selectin expressed on the surface of endothelial cells aids in the recruitment of neutrophils to the testis. Once neutrophils are bound to endothelial cells they can transmigrate through the endothelial cells into the interstitium where they are poised to release factors such as reactive oxygen species or other cytokines. The source of IL-1β production after ischemia/reperfusion of the testis is currently unkown; however, Sertoli cells, Leydig cells, and interstitial macrophages are candidates.
Mentions: As early as 0.5 hr after IR of the murine testis an increase in the expression of both TNFα and IL-1β is observed [22] and this precedes the activation of JNK. JNK is a stress-related kinase that plays a critical role in the cellular response to many types of cellular stress. Two transcription factors downstream of JNK, ATF-2 and c-jun, are also activated, and immunolocalization of activated, phosphorylated, JNK (phospho-JNK) demonstrated immunoreactivity in intratesticular blood vessels [22]. Corresponding with this was an increase in E-selectin mRNA and protein 4 hr after IR of the testis [22]. Indeed, the E-selectin promoter is known to contain a positive regulatory domain II site which has been shown to bind a heterodimer of ATF-2 and c-jun [81]. 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 E-selectin in endothelial cells and ultimately neutrophil recruitment (Figure 1). In order to determine if TNFα, IL-1β, or both proinflammatory cytokines were eliciting this response, the cytokines were injected either alone or in combination to the testis and phosphorylation of JNK and neutrophil recruitment was examined. Results from these experiments revealed that injection of IL-1β mimicked the effects of IR on the testis, causing an activation of JNK and a recruitment of neutrophils to the testis [22]. Thus, an increase in IL-1β after IR of the testis stimulates an intracellular signaling cascade in testicular endothelial cells resulting in neutrophil recruitment and eventually germ cell death. The cell type responsible for the increase in IL-1β production after IR of the testis is currently unknown. Even though TNFα did not have a role in neutrophil recruitment or JNK activation in the testis, preliminary experiments in our lab suggest that the increase in TNFα may lead to the activation of NFκB in Sertoli cells (Lysiak and Turner, unpublished) and may influence germ cell apoptosis by increasing FasL expression in Sertoli cells. Identification of the mechanisms involved in germ cell-specific apoptosis after IR may lead to the development of therapies aimed at interrupting specific pathways in order to prevent the IR-induced loss of spermatogenesis.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, University of Virginia, Charlottesville, VA 22908, USA. jl6n@virginia.edu

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.

Show MeSH
Related in: MedlinePlus