Treatment with testosterone or estradiol in melatonin treated females and males MRL/MpJ‐Fas^lpr mice induces negative effects in developing systemic lupus erythematosus

Abstract

MRL/MpJ-Fas(lpr) mice is widely accepted as a valuable model of systemic lupus erythematosus. As described in a previous work, the incidence of lupus in this strain is determined by sex hormones, i.e., estrogens and androgens. Moreover, we reported that the immunomodulatory action of melatonin in these mice was gender-dependent probably through modulation and inhibition of sex hormones. Herein, we performed an experiment using hormone therapy, by treating female MRL-lpr mice with testosterone and males with estradiol and with melatonin. A decrease in total serum immunoglobulin (Ig)G and IgM immunoglobulin titers, anti-double-stranded DNA, and anti-CII autoantibodies in female mice treated with both melatonin and testosterone was revealed, along with an increase in pro-inflammatory cytokines [interleukin (IL)-2, IL-6, interferon-gamma, tumor necrosis factor-alpha, and IL-1beta), nitrite/nitrate and a decrease in anti-inflammatory cytokines (IL-10). Melatonin and estradiol treatment exhibited a similar effect in male mice. Autoantibody titer elevation and pro-inflammatory versus anti-inflammatory cytokine prevalence degraded all immunological parameters. Similar results were obtained when spleen and lymph node lymphocytes were cultured. Again, melatonin and testosterone treatment stimulated pro-inflammatory and reduced anti-inflammatory cytokines produced by lymphocytes in females. The effect was similar in males treated with melatonin and estradiol. In summary, we observed that although melatonin alone prevents lupus development in females, adding testosterone, increased pro-inflammatory cytokine pattern. In contrary, estradiol-treated males did not show any decrease in pro-inflammatory cytokines but showed an increase in regard to melatonin controls. These findings confirm that melatonin action in MRL/MpJ-Fas(lpr) mice could be gender-dependent through modulation of sex hormones.

An update on diet and nutritional factors in systemic lupus erythematosus management

“…In MRL/lpr mice treated with the same amount of melatonin and hormone therapy, adding testosterone to female mice and oestradiol to males, melatonin alone prevented lupus development in females, but the addition of testosterone to melatonin-treated female mice produced a similar negative pattern to that observed previously in male lupus mice. These effects were similar in oestradiol-treated males, confirming that melatonin action in MRL/lpr mice could be sex dependent through the modulation of sex hormones ( 192 ) . Furthermore, melatonin treatment (0·01, 0·1, 1·0 mg/kg) in pristane-induced SLE BALB/c mice antagonised the increasing levels of IgM, anti-single-stranded DNA and histone autoantibodies and decreased renal lesions caused by pristane.…”

Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice

“…This notion has been further validated by our observation that microbiota depletion has no impact on autoimmunity and disease incidence in male SNF1 mice. In fact, although impact on gut microbiota was not assessed, previous reports have shown that androgen contributes to slower disease progression and lower lupus-like incidence lupus-prone mice [47,60,61] Overall, our study, for the first time, demonstrates distinct roles for gut microbiota in lupusprone female and male mice contributing to gender bias in the disease outcomes. In females, gut microbiota appears to have composition-independent, gut mucosa interaction-dose dependent, role in promoting intestinal pro-inflammatory immune response and eventual systemic autoimmunity.…”

Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases

“…Their data indicated that administration of melatonin has a gender-dependent dichotomous effect in MRL- Fas lpr mice in the early stages of disease. A later study presented by the same authors confirmed that this gender-dependent effect of melatonin in MRL- Fas lpr mice is through modulation of sex hormones [85]. …”