Dihydrotestosterone Inhibits Interleukin-1.ALPHA. or Tumor Necrosis Factor .ALPHA.-Induced Proinflammatory Cytokine Production via Androgen Receptor-Dependent Inhibition of Nuclear Factor-.KAPPA.B Activation in Rheumatoid Fibroblast-Like Synovial Cell Line

Xu, Jin; Itoh, Yoshio; Hayashi, Hidetoshi; Takii, Takemasa; Miyazawa, Keiji; Onozaki, Kikuo

doi:10.1248/bpb.34.1724

Cited by 24 publications

(14 citation statements)

References 28 publications

(31 reference statements)

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“…We measured TNF-␣ and found that the levels were attenuated in testosterone-treated I/R rats compared with untreated rats with I/R injury. Androgens have been shown previously to be anti-inflammatory (9,19,35). For example, DHT, via the androgen receptor, inhibits IL-1␣ and TNF-␣-induced proinflammatory cytokine production in a rheumatoid cell line (35), and LPS treatment caused increased proinflammatory cytokines in a model of androgen ablation (19).…”

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

“…Androgens have been shown previously to be anti-inflammatory (9,19,35). For example, DHT, via the androgen receptor, inhibits IL-1␣ and TNF-␣-induced proinflammatory cytokine production in a rheumatoid cell line (35), and LPS treatment caused increased proinflammatory cytokines in a model of androgen ablation (19). Because TNF-␣ is produced by nonimmune cells in the kidney, such as medullary thick ascending limb, the reduction in TNF-␣ may not be contributory to the protection caused by testosterone, but may simply be an indication of less injury to the medulla in the presence of testosterone.…”

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

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Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Soljancic

Ruiz

Chandrashekar

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-␣ and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol. kidney injury molecule-1; sex; androgens; vascular endothelial growth factor ACUTE KIDNEY INJURY (AKI) is thought to affect ϳ2-5% of all hospitalized individuals in the United States (31a), and the mortality rates are as high as 80% (5, 11, 31). Aging increases both the incidence and the mortality rates due to AKI in both men and women. Despite the importance of the problem, the mechanisms responsible for AKI have not been completely elucidated.The incidence of acute renal failure in surgical patients is significantly higher in men than women (8,16,20). Animal studies have also reported sex differences in the adverse effects of ischemia reperfusion (I/R) of the kidney with males being more susceptible than females (18, 21). The mechanisms responsible for the sex differences in AKI in humans and the sex differences in animals are not clear.Reductions in serum testosterone in men have been shown in numerous studies to occur with chronic disease, such as heart disease, obesity, hypertension, and renal disease (2, 13, 15, 24). The association of reduction in testosterone with increased cardiovascular disease has lead investigators to suggest that it is the reduction in testosterone that may contribute to chronic disease states rather than that the chronic disease is the cause of the reduction in circulating testosterone levels (15). There is also evidence that acute conditions may reduce androgen levels. For example, Pugh et al. (23) and Tripathi and Hegde (30...

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Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Soljancic

Ruiz

Chandrashekar

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Aberrant AR activity has been linked with several pathological conditions including male infertility, androgen insensitivity syndrome, spinal and bulbar muscular atrophy, rheumatoid arthritis, hirsutism, baldness, acne, breast and PCa (Gao & Chen 2013, Xu et al 2011). Huggins and Hodges (Huggins & Hodges 1941) first showed the correlation between androgen and prostate tumor growth and based on this pioneer study, ADT became the key treatment method.…”

Section: :12mentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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“…In addition, previous studies have identified the promoter region of MMP1, including the binding site of the transcription factors activator protein-1 (AP-1) and CRE-binding protein (Chambers et al 2013;Reunanen et al 2002). Among them, AP-1 is known to be regulated by TNF-a and IL-1 via nuclear factor-kappa B and Nuclear factor NF-kappa-B inhibitor kinase signalling in several fibroblasts (Cheng et al 2009;Xu et al 2011). Therefore, AP-1 seems to be a candidate transcription factor for the regulation of fibrotic gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…This effect was observed using primary HSCs obtained from the liver of two different patients, indicating a generic response between patients. MMP1 gene expression is reported to be induced by TNF-a in many types of fibroblasts (Sasaki et al 2000;Xu et al 2011). However, in our primary HSCs, TNF-a barely induced MMP1 expression.…”

Section: Effect Of Inflammatory Cytokines On Primary Hscsmentioning

confidence: 99%

Regulation of matrix metalloproteinase-1 and alpha-smooth muscle actin expression by interleukin-1 alpha and tumour necrosis factor alpha in hepatic stellate cells

et al. 2016

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Hepatic stellate cells (HSCs) are key players in liver fibrosis and regeneration via collagen degradation and synthesis. These phenomena involve inflammatory cytokines released from non-parenchymal liver cells such as Kupffer cells. Although the effects of individual cytokines on many cell types have been investigated in various conditions, such as inflammation and tissue fibrosis, investigating the effect of combined cytokines would further our understanding of the regulatory mechanisms in tissue fibrosis. Here, we report the effect of multiple cytokine combinations on primary HSCs. We first examined the effect of individual cytokines and then the simultaneous exposure of different cytokines, including interleukin-6 (IL-6), IL-1 alpha (IL-1α), platelet-derived growth factor (PDGF), tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β), on matrix metalloproteinase-1 (MMP1) gene expression in primary HSCs. We observed that the combination of all five cytokines induced higher levels of MMP1 gene expression. Of these cytokines, TNF-α and IL-1α were found to be the key cytokines for not only inducing MMP1 expression, but also increasing α-smooth muscle actin gene expression. In conclusion, the combined treatment of TNF-α and IL-1α on HSCs had an enhanced effect on the expression of the fibrotic genes, MMP1 and α-smooth muscle actin, so appears to be an important regulator for tissue regeneration. This finding suggests that stimulation with combined anti-fibrotic cytokines is a potential approach in the development of a novel therapy for the recovery of liver fibrosis.

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Dihydrotestosterone Inhibits Interleukin-1.ALPHA. or Tumor Necrosis Factor .ALPHA.-Induced Proinflammatory Cytokine Production via Androgen Receptor-Dependent Inhibition of Nuclear Factor-.KAPPA.B Activation in Rheumatoid Fibroblast-Like Synovial Cell Line

Cited by 24 publications

References 28 publications

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Regulation of matrix metalloproteinase-1 and alpha-smooth muscle actin expression by interleukin-1 alpha and tumour necrosis factor alpha in hepatic stellate cells

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