Testosterone inhibits expression of inducible nitric oxide synthase in murine macrophages

Friedl, Roswitha; Brunner, Monika; Moeslinger, Thomas; Spieckermann, P. G.

doi:10.1016/s0024-3205(00)00953-x

Cited by 78 publications

(48 citation statements)

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“…Testosterone has been reported to inhibit the expression of inducible nitric oxide synthase after lipopolysaccharide stimulation in RAW264.7 cells. 48 Testosterone has also been reported to decrease toll-like receptor 4 expression in these cells. 49 Babesia has not been reported to stimulate toll-like receptor 4, but expression of other receptors that sense Babesia antigens might be reduced by testosterone.…”

Section: Discussionmentioning

confidence: 95%

Effect of Sex Steroids on Babesia microti Infection in Mice

Sasaki¹,

Fujii²,

Iwamoto³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. Sex-based-differences are known to affect susceptibility to protozoan infections, but their effects on parasitemia and clinical symptoms in Babesia infections remain unclear. We examined the sex-based susceptibility of various mouse strains to Babesia microti Munich strain infection. In all strains, male mice exhibited significantly higher peak parasitemia and more severe anemia than female mice. Testosterone and estradiol-17β treatment caused an increase in parasitemia and aggravation of anemia. Orchidectomized male mice receiving testosterone exhibited smaller splenic macrophage populations three days after infection, smaller B cell populations 10 days after infection, and reduced splenic tumor necrosis factor-α and interferon-γ mRNA expression than mice that did not receive testosterone. Mice receiving estradiol-17β did not exhibit immunosuppressive effects. Thus, a weakened and delayed innate immunity response may lead to acquired immunity failure. The results suggested that testosterone directly affects T or B cells, leading to delayed acquired immunity, dramatically increased parasitemia, and severe anemia.

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Section: Discussionmentioning

confidence: 95%

Effect of Sex Steroids on Babesia microti Infection in Mice

Sasaki¹,

Fujii²,

Iwamoto³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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“…Indeed, a report by Hayashi et al (30), using a macrophage cell line (J774) in culture, showed that estrogen would inhibit the induction of iNOS by LPS ϩ IFN-␥. However, Friedl et al (31) reported that testosterone inhibited the induction of iNOS in the murine macophage RAW264.7 cell line. These in vitro data by Friedl showing that testosterone inhibited iNOS induction contradict our in vivo data and could reflect in vivo vs in vitro differences in macrophage function.…”

Section: Discussionmentioning

confidence: 99%

An Inducible Nitric Oxide Synthase-Luciferase Reporter System for In Vivo Testing of Anti-inflammatory Compounds in Transgenic Mice

Zhang

Weber

et al. 2003

The Journal of Immunology

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The inducible NO synthase gene (iNOS) plays a role in a number of chronic and acute conditions, including septic shock and contact hypersensitivity autoimmune diseases, such as rheumatoid arthritis, gastrointestinal disorders, and myocardial ischemia. The iNOS gene is primarily under transcriptional control and is induced in a variety of conditions. The ability to monitor and quantify iNOS expression in vivo may facilitate a better understanding of the role of iNOS in different diseases. In this study, we describe a transgenic mouse (iNos-luc) in which the luciferase reporter is under control of the murine iNOS promoter. In an acute sepsis model produced by injection of IFN-γ and LPS, we observed an induction of iNOS-driven luciferase activity in the mouse liver. This transgene induction is dose and time dependent and correlated with an increase of liver iNOS protein and iNOS mRNA levels. With this model, we tested 11 compounds previously shown to inhibit iNOS induction in vitro or in vivo. Administration of dexamethasone, epigallocatechin gallate, α-phenyl-N-tert-butyl nitrone, and ebselen significantly suppressed iNOS transgene induction by IFN-γ and LPS. We further evaluated the use of the iNos-luc transgenic mice in a zymosan-induced arthritis model. Intra-articular injection of zymosan induced iNos-luc expression in the knee joint. The establishment of the iNos-luc transgenic model provides a valuable tool for studying processes in which the iNOS gene is induced and for screening anti-inflammatory compounds in vivo.

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“…NO, the product of NO synthases (NOSs), possesses anti-inflammatory and vasodilative activity and is anti-apoptotic through Akt signaling pathways (13)(14)(15)(16)(17). Sex hormones are known to regulate NO synthesis (18,19).…”

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confidence: 99%

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

Park

Kim

Ahn

et al. 2004

Journal of Biological Chemistry

302

273

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Female mice are much more resistant to ischemia/ reperfusion (I/R)-induced kidney injury when compared with males. Although estrogen administration can partially reduce kidney injury associated with I/R, we demonstrated that the presence of testosterone, more than the absence of estrogen, plays a critical role in gender differences in susceptibility of the kidney to ischemic injury. Testosterone administration to females increases kidney susceptibility to ischemia. Dihydrotestosterone, which can not be aromatized to estrogen, has effects equal to those of testosterone. Castration reduces the I/R-induced kidney injury. In contrast, ovariectomy does not affect kidney injury induced by ischemia in females. Testosterone reduces ischemia-induced activation of nitric oxide synthases (NOSs) and Akt and the ratio of extracellular signal related kinase (ERK) to c-jun N-terminal kinase (JNK) phosphorylation. Pharmacological (N -nitro-L-arginine) or genetic (endothelial NOS or inducible NOS) inhibition of NOSs in females enhances kidney susceptibility to ischemia. Nitric oxide increases Akt phosphorylation and protects MadinDarby canine kidney epithelial cells from oxidant stress. Antagonists of androgen or estrogen receptors do not affect the gender differences. In conclusion, testosterone inhibits the post-ischemic activation of NOSs and Akt and the ratio of ERK to JNK phosphorylation through non-androgen receptor-medicated mechanisms, leading to increased inflammation and increased functional injury to the kidney. These findings provide a new paradigm for the design of therapies for ischemia/ reperfusion injury and may be important to our understanding of the pathophysiology of acute renal failure in pregnancy where plasma androgen levels are elevated.

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Testosterone inhibits expression of inducible nitric oxide synthase in murine macrophages

Cited by 78 publications

References 0 publications

Effect of Sex Steroids on Babesia microti Infection in Mice

Effect of Sex Steroids on Babesia microti Infection in Mice

An Inducible Nitric Oxide Synthase-Luciferase Reporter System for In Vivo Testing of Anti-inflammatory Compounds in Transgenic Mice

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

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