Involvement of Tumor Necrosis Factor-α in the Pathogenesis of Autoimmune Orchitis in Rats1

Suescun, María Olga; Rival, Claudia; Theas, María Susana; Calandra, Ricardo S.; Lustig, Livia

doi:10.1095/biolreprod.102.011189

Cited by 93 publications

(81 citation statements)

References 31 publications

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“…TNFa and chemokines (mainly, macrophage inflammatory protein-1b (MIP-1b), interleukin (IL)-8 and regulated on activation, normal T cell expressed and secreted (RANTES)) present in the vicinity of blood vessel walls or present intravascularly can rapidly activate the CD44 molecule expressed on T cells (Ariel et al 2000). These factors could be involved in the activation of CD44 in lymphomononuclear cells in EAO since we previously demonstrated an increase in TNFa (Suescun et al 2003) and MIP-1b (Guazzone et al 2002) concentration in conditioned media from testicular macrophages of rats with severe orchitis. In addition it has been reported (Mohamadzadeh et al 1998) that TNFa and IL-1b induce the expression of HA in endothelial cells of microvessels.…”

Section: Discussionmentioning

confidence: 92%

“…The total number of fields counted for each section was 40, and three animals/group per day after the first immunization were studied. The number of CD44 þ cells per unit volume testis was calculated as previously described (Suescun et al 2003) using the Floderus equation (Floderus 1944).…”

Section: Immunohistochemical Techniquesmentioning

confidence: 99%

“…We previously described an experimental model of EAO in rats (Doncel et al 1989) characterized by an increased number of immune cells in the testicular interstitium and different degrees of germ cell apoptosis and sloughing in the seminiferous tubules (Lustig et al 1993, Suescun et al 2003. We also showed that monocyte chemoattractant protein-1 (MCP-1) is highly expressed in testicular interstitial cells, suggesting that this chemokine has an important role in recruiting immune cells to the testis in rats undergoing autoimmune orchitis (Guazzone et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of CD44 in leukocyte recruitment to the rat testis in experimental autoimmune orchitis

Guazzone¹,

Denduchis²,

Lustig³

2005

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Experimental autoimmune orchitis (EAO) is characterized by an interstitial mononuclear cell infiltrate and a severe lesion of the seminiferous tubules with germ cells that undergo apoptosis and sloughing. The aim of this study was to determine the role of CD44 in testicular leukocyte recruitment in EAO. The biological functions of CD44 have been attributed to the generation of a functionally active hyaluronan-binding phenotype. Orchitis was induced in Sprague-Dawley adult rats by active immunization with an emulsion of testicular homogenate and complete Freund's adjuvant using Bordetella pertussis as co-adjuvant. Control rats (C) injected with saline and adjuvants and normal (N) untreated rats were also studied. CD44 expression was analyzed by flow cytometry in peripheral blood mononuclear cells (PBMC) and lymph node cells isolated from rats at different times after the first immunization. We observed an increase in the mean fluorescence intensity of both samples in the C and experimental (E) groups only after the immunization period. A significant decrease in percentage of CD44 1 PBMC and in mean fluorescence intensity was observed in rats with orchitis compared with the C group. By in vitro hyaluronic acid-binding assay we demonstrated that the percentage of PBMC adhesion was higher in the E group compared with the C and N groups. By immunohistochemistry, we observed a significant increase in the number of CD44 1 cells in the testicular interstitium of rats with severe orchitis compared with the N and C groups. These results suggested that the CD44 molecule is involved in the homing of lymphomonocytes into the testes of rats with autoimmune orchitis.

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Section: Discussionmentioning

confidence: 92%

Section: Immunohistochemical Techniquesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of CD44 in leukocyte recruitment to the rat testis in experimental autoimmune orchitis

Guazzone¹,

Denduchis²,

Lustig³

2005

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“…Thus, microenvironment stimuli regulate the specificity of leukocyte recruitment (Cook-Mills et al 2010). In fact testicular immune cells secrete proinflammatory cytokines such as TNF-a (Suescun et al 2003) and IL6 (Rival et al 2006b), and nitric oxide (NO) production and NO synthase activity increased in testis of EAO compared to C and N rats (Jarazo Dietrich et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The total number of fields counted for each section was 40, and 3 animals/group/day after first immunization were analyzed. The number of CCR5C or CCR1C cells per unit volume testis was calculated by morphometry, as previously described (Suescun et al 2003) using the Floderus Default (Floderus 1944). Illustration of CCR5C cells was published in our previous report on chemokines ) since CCR5 is also the receptor for CCL4.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Expression of cell adhesion molecules, chemokines and chemokine receptors involved in leukocyte traffic in rats undergoing autoimmune orchitis

Guazzone

Jacobo²,

Denduchis³

et al. 2012

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The testis is considered an immunologically privileged site where germ cell antigens are protected from autoimmune attack. Yet in response to infections, inflammatory diseases, or trauma, there is an influx of leukocytes to testicular interstitium. Interactions between endothelial cells (EC) and circulating leukocytes are implicated in the initiation and evolution of inflammatory processes. Chemokines are a family of chemoattractant cytokines characterized by their ability to both recruit and activate cells. Thus, we investigated the expression of CCL3, its receptors, and adhesion molecules CD31 and CD106 in an in vivo model of experimental autoimmune orchitis (EAO). In EAO, the highest content of CCL3 in testicular fluid coincides with onset of the disease. However, CCL3 released in vitro by testicular macrophages is higher during the immunization period. The specific chemokine receptors, CCR1 and CCR5, were expressed by testicular monocytes/macrophages and an increased number of CCR5C cells was associated with the degree of testicular lesion. EC also play an essential role by facilitating leukocyte recruitment via their ability to express cell surface adhesion molecules that mediate interactions with leukocytes in the bloodstream. Rats with EAO showed a significant increase in the percentage of CD31C EC that upregulate the expression of CD106. The percentage of leukocytes isolated from peripheral blood and lymph nodes expressing CD49d (CD106 ligand) also increases during orchitis. These data suggest that cell adhesion molecules, in conjunction with chemokines, contribute to the formation of a chemotactic gradient within the testis, causing the leukocyte infiltration characteristic of EAO histopathology.

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Cytokines and chemokines in testicular inflammation: A brief review

Guazzone

Jacobo

Theas

et al. 2009

Microscopy Res & Technique

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171

128

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A wide spectrum of data in the literature shows the relevance of cytokines as paracrine regulators of spermatogenesis and steroidogenesis in the normal testis. In this brief review, we highlight the relevance of cytokines in the testis during inflammation. This phenomenon involves complex and multiple interactions among immune and germ cells generally resulting in the alteration of spermatogenesis. The complexity of these cell interactions is multiplied because Sertoli and Leydig cells are also producers of pro- and anti-inflammatory cytokines and chemokines. Also, cytokines are pleiotropic and they exert opposite and/or redundant effects in different conditions. However, in spite of this bidirectional immunoregulatory function of cytokines, the mass of the data, reported from experiments of acute testicular inflammation, shows upregulation of interleukin (IL)-1beta, IL-1alpha, IL-6, and tumor necrosis factor alpha (TNF-alpha), which induce adverse effects on germ cells. In autoimmune orchitis, a chronic testicular inflammation, chemokines such as CCL2, CCL3, and CCL4 induce attraction and extravasation of immune cells within the testicular interstitium. These cells alter the normal immunosuppressor microenvironment principally through the secretion of proinflammatory cytokines, interferon-gamma initially, and IL-6 and TNF-alpha thereafter. Germ cells expressing TNFR1, IL-6R, and Fas increase in number and undergo apoptosis, through the TNF-alpha/TNFR1, IL-6/IL-6R, and Fas/Fas L systems. The knowledge of immune-germ and somatic testicular cell interactions will contribute to the understanding of the mechanisms by which chronic inflammatory conditions of the testis can disrupt the process of spermatogenesis.

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Involvement of Tumor Necrosis Factor-α in the Pathogenesis of Autoimmune Orchitis in Rats1

Cited by 93 publications

References 31 publications

Involvement of CD44 in leukocyte recruitment to the rat testis in experimental autoimmune orchitis

Involvement of CD44 in leukocyte recruitment to the rat testis in experimental autoimmune orchitis

Expression of cell adhesion molecules, chemokines and chemokine receptors involved in leukocyte traffic in rats undergoing autoimmune orchitis

Cytokines and chemokines in testicular inflammation: A brief review

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