Extracellular inosine modulates ERK 1/2 and p38 phosphorylation in cultured Sertoli cells: Possible participation in TNF-alpha modulation of ERK 1/2

Cheng

American Journal of Physiology-Cell Physiology

et al. 2013

The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 μmol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) were 0.125 ± 0.020 μmol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) plus guanosine (30 μmol/l) were 1.173 ± 0.061 μmol/l, indicating slow disposition of extracellular adenosine. Cell injury increased extracellular levels of endogenous adenosine and guanosine, and the effects of cell injury on endogenous extracellular adenosine were modulated by altering the levels of endogenous extracellular guanosine with exogenous purine nucleoside phosphorylase (converts guanosine to guanine) or 8-aminoguanosine (inhibits purine nucleoside phosphorylase). Extracellular guanosine also slowed the disposition of extracellular adenosine in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts, and kidney epithelial cells and in human aortic and coronary artery vascular smooth muscle cells and coronary artery endothelial cells. The effects of guanosine on adenosine levels were not mimicked or attenuated by 5-iodotubericidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)-adenine (adenosine deaminase inhibitor), 5-aminoimidazole-4-carboxamide (guanine deaminase inhibitor), aristeromycin (S-adenosylhomocysteine hydrolase inhibitor), low sodium (inhibits concentrative nucleoside transporters), S-(4-nitrobenzyl)-6-thioinosine [inhibits equilibrative nucleoside transporter (ENT) type 1], zidovudine (inhibits ENT type 2), or acadesine (known modulator of adenosine levels). Guanosine also increases extracellular inosine, uridine, thymidine, and cytidine, yet decreases extracellular uric acid. In conclusion, extracellular guanosine regulates extracellular adenosine levels.

Section: Discussionmentioning

confidence: 99%

Extracellular guanosine regulates extracellular adenosine levels

Cheng

American Journal of Physiology-Cell Physiology

et al. 2013

“…Extracellular ATP and its breakdown product adenosine are both involved in this process after ATP and adenosine are released from Sertoli cells during paracrine regulation of the maturation process [141]. Extracellular inosine increases ERK1/2 and p38 phosphorylation in Sertoli cells, possibly through A 1 receptor activation [383]. Sertoli cells are key cells in the development and maintenance of stem cell spermatogenesis as well as in the secretion of ATP activated Cl − -and K + -rich fluid into the lumen of seminiferous tubules [20].…”

Section: Testismentioning

confidence: 99%

Purinergic signalling in the reproductive system in health and disease

Burnstock

2013

Purinergic Signalling

There are multiple roles for purinergic signalling in both male and female reproductive organs. ATP, released as a cotransmitter with noradrenaline from sympathetic nerves, contracts smooth muscle via P2X1 receptors in vas deferens, seminal vesicles, prostate and uterus, as well as in blood vessels. Male infertility occurs in P2X1 receptor knockout mice. Both short-and long-term trophic purinergic signalling occurs in reproductive organs. Purinergic signalling is involved in hormone secretion, penile erection, sperm motility and capacitation, and mucous production. Changes in purinoceptor expression occur in pathophysiological conditions, including pre-eclampsia, cancer and pain.

Journal of Endocrinology

“…Additionally, a recent study has shown that TNFa also induces nitric oxide and inosine production by Sertoli cells, protecting these cells against hydrogen peroxide-induced damage via the ERK1/2 signaling pathway (Souza et al 2005). Recent studies have also shown that nitric oxide regulates Sertoli cell TJ-barrier function via the cGMP/PKG signaling pathway (Lee & Cheng 2003).…”

Section: Figure 7 (A)-(j)mentioning

confidence: 99%

Tumor necrosis factor α reversibly disrupts the blood–testis barrier and impairs Sertoli–germ cell adhesion in the seminiferous epithelium of adult rat testes

Li¹,

Xia²,

Mruk³

et al. 2006

182

184

The timely restructuring of the blood-testis barrier (BTB) that facilitates the migration of preleptotene and leptotene spermatocytes from the basal to the adluminal compartment in the seminiferous epithelium of adult rat testes, which occurs at late stage VII through early stage VIII of the epithelial cycle, is a crucial cellular event of spermatogenesis. However, the regulation of BTB dynamics at the biochemical level remains elusive. In this study, tumor necrosis factor a (TNFa), a secretory product of Sertoli and germ cells in rat testes, was shown to affect junction dynamics in vivo.Following an acute administration of recombinant TNFa directly to adult rat testes in vivo at 0$5 and 2 mg/testis (with a body weight w300 g), this treatment significantly and transiently disrupted the BTB. It also transiently inhibited the steady-state protein levels of occludin, zonula occludens-1, and N-cadherin, but not junction adhesion molecule-A, a-, and b-catenin in testes at the BTB site as illustrated by immunoblottings, immunohistochemistry, electron microscopy, and fluorescent microscopy. This transient disruption of the BTB integrity induced by TNFa treatment was further demonstrated by a functional test to assess the passage of a fluorescent dye (e.g. fluorescein-5-isothiocyanate) from the systemic circulation to the adluminal compartment. Additionally, both the phosphorylated-Ser/Thr protein kinase activated by MAP kinase kinase (p-p38) and phosphorylated-externally regulated kinase (p-ERK) mitogen -activated protein kinase-signaling pathways were transiently activated. Collectively, these data coupled with the recently published in vitro studies have illustrated that the BTB is likely utilizing a novel mechanism in which localized production of TNFa by Sertoli and germ cells into the microenvironment at the basal compartment facilitates the timely restructuring ('opening'?) of the BTB during spermatogenesis to facilitate germ cell migration.