TWEAK participates in various cellular effects by engaging its receptor of Fn14. Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis, or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown. In this study, we found an elevated serum level of TWEAK and a positive correlation between serum TWEAK and anti-BP180 antibodies. Immunohistochemistry showed strong TWEAK and Fn14 expression and implied an opposite relationship between the TWEAK and BP180 expression in skin samples from BP patients. In vitro TWEAK stimuli reduced BP180 expression in HaCaT cells and inhibited the adhesion of cells to the culture dish. Consistently, the transfection of Fn14 small interfering RNA preserved BP180 and protected cells from losing adherence. Moreover, such effect of TWEAK correlated with activation of the extracellular signal-regulated kinase and NF-κB pathways and downstream ADAMs. By silencing ADAM17 with small interfering RNA, we showed that ADAM17 participated in TWEAK-induced BP180 loss. Therefore, TWEAK may contribute to the pathogenesis of BP by reducing BP180 expression and cellular adherence, involving the activation of ERK and NF-κB pathways. TWEAK may serve as a biomarker or therapeutic target of BP.
Abstract. The purpose of this study was to investigate seasonal changes of spermatogenesis and the cellular localization of P450c17 and P450arom in wild male ground squirrels during the breeding and non-breeding seasons. The testicular weight, testicular size and score count of spermatogenesis from April to September were measured, and histological and immunohistochemical observations of testicular tissues were performed in wild male ground squirrels. In addition, total proteins were extracted from testicular tissue in the breeding and non-breeding seasons and were used for Western blotting analysis for P450c17 and P450arom. There were marked variations in testicular weight, testicular size and score count of spermatogenesis from the breeding season (April) to the non-breeding season (September). Histologically, spermatogonia, primary spermatocytes, secondary spermatocytes and spermatozoa were identified in the breeding season (April). Immunolocalization of P450c17 was detected in Leydig cells and spermatozoa during the breeding season and was only found in Leydig cells during the non-breeding season. The positive signals of P450c17 by Western blotting were both observed in the breeding and non-breeding seasons. Immunolocalization of P450arom was observed in Leydig cells, Sertoli cells and all types of spermatogenic cells including mature-phase spermatozoa in the breeding season, while immunoreactivity for P450arom was not present in the testis of the non-breeding season. With P450arom antibody, a band was also only detected in the breeding season by Western blotting. These results suggest that the seasonal changes in testicular weight and size are correlated with spermatogenesis and immunolocalization of P450c17 and P450arom, and androgen and estrogen may play an important role in the spermatogenesis and testicular recrudescence and regression process. Key words: Ground squirrel, Immunolocalization, P450c17, P450arom, Spermatogenesis (J. Reprod. Dev. 56: [297][298][299][300][301][302] 2010) he reproductive strategies of seasonal breeders are adaptations to annual changes in the environment, and they minimize the animals' energetic efforts for reproduction. Mature males show synchronized cycles of testicular growth and involution between the breeding and non-breeding periods [1]. Seasonal changes of testicular steroidogenesis and spermatogenesis in wild animals have been reported in many species, including American black bears [2], Japanese raccoon dogs [3], Japanese black bears [4], Northern fur seals [5] and polar bears [6]. In these wild animals, immunohistochemical studies on testicular tissues have demonstrated that the distributions of immunoreactivities for steroidogenic enzymes in testicular tissue are associated with seasons and species.It is well known that normal testicular development and maintenance of spermatogenesis are controlled by gonadotropins and testosterone, whose effects are modulated by locally-produced factors, and among them, with estrogen being the main factor involved [7]. Testoste...
BackgroundIschemic stroke-induced neuroinflammation is mainly mediated by microglial cells. The nuclear factor kappa B (NF-κB) pathway is the key transcriptional pathway that initiates inflammatory responses following cerebral ischemia. OTULIN, a critical negative regulator of the NF-κΒ signaling pathway, exerts robust effects on peripheral immune cell-mediated inflammation and is regarded as an essential mediator for repressing inflammation in vivo. The effect of OTULIN on inflammatory responses in the central nervous system (CNS) was previously unstudied. This current study investigated the anti-inflammatory effect of OTULIN both in vitro and in vivo in ischemic stroke models.MethodsSprague-Dawley (SD) rats were subjected to transient middle cerebral artery occlusion (tMCAO) or an intraperitoneal injection of lipopolysaccharide (LPS). Overexpression of the OTULIN gene was utilized to observe the effect of OTULIN on ischemic stroke outcomes. The effect of OTULIN overexpression on microglia-mediated neuroinflammation was examined in rat primary microglia (PM) and in the microglial cell line N9 after induction by oxygen-glucose deprivation (OGD)-treated neuronal medium. The activation and inflammatory responses of microglia were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting.ResultsIn the tMCAO rats, the focal cerebral ischemia/reperfusion injury induced a continuous increase in OTULIN expression within 72 h, and OTULIN expression was increased in activated microglial cells. OTULIN overexpression obviously decreased the cerebral infarct volume, improved the neurological function deficits, and reduced neuronal loss at 72 h after reperfusion, and it also inhibited the activation of microglia and attenuated the release of TNF-α, IL-1β, and IL-6 by suppressing the NF-κB pathway at 24 h after tMCAO. In vitro, OTULIN overexpression inhibited the microglia-mediated neuroinflammation by reducing the production of TNF-α, IL-1β, and IL-6 via depressing the NF-κB pathway in both PM and N9 cells.ConclusionsOTULIN provides a potential therapeutic target for ischemic brain injury by ameliorating the excessive activation of microglial cells and neuroinflammation through repressing the NF-κB signaling pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1117-5) contains supplementary material, which is available to authorized users.
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