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it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells

In cycling women, the largest quantities of Ig were detected before ovulation

In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors

E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors

In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life

Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases

IFN-γ, IL-12, and TNF were allocated to Th1 reactions

IL-4, IL-5, and IL-10 to Th2 responses

antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17

no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.

So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.

Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation

in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells

In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity

increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response

secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels

The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations

experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.

E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal

It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation

important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF

low E2 concentrations were demonstrated to have no or even stimulatory effects

This renders a woman in the postmenopausal phase to a more proinflammatory situation

most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels

E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy

Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat

It is produced predominately by antigen-simulated CD4+ T cells, while it can also be produced by CD8+ cells, natural killer (NK) cells, and activated dendritic cells (DC)

IL-2 is an important factor for the maintenance of CD4+ regulatory T cells

plays a critical role in the differentiation of CD4+ T cells into a variety of subsets

It can promote CD8+ T-cell and NK cell cytotoxicity activity, and modulate T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) differentiation

Of note, Tregs, which act to dampen the immune response, constitutively express high levels of α chain

IL-2Rα is unique to IL-2 and is expressed by a number of immune cells including T regulatory cells (Treg), activated CD4+ and CD8+T cells, B cells, mature DCs, endothelial cells

some investigators evaluated the efficacy of regimens containing low-dose IL-2

IL-2 can promote the activation and cell growth of T and NK cells

Unfortunately, not all of patients would benefit from targeted therapy and nearly all patients who initially respond to targeted inhibitors inevitably develop acquired resistance to the treatment

IL-2 also stimulates T-regulatory cells that constitutively express CTLA-4 and can suppress immune reactions. Hence, IL-2 might enhance antitumor reactivity in the presence of CTLA-4 blockade

both HD and low-dose IL-2 therapy preferentially induce the expansion of CD4+CD25+Foxp3+ Treg and the Treg level remains elevated after each cycle of HD IL-2 therapy

Due to rapid elimination and metabolism via the kidney, IL-2 has a short serum half-life of several minutes

HD IL-2-induced severe toxicities including vascular leak syndrome (VLS), pulmonary edema, hypotension, and heart toxicities

dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice

These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health

all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.

The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.

feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight

mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique

Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles

the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's

The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months

mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed

blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics

previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling

Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice

Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls

xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls

Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism

One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells

Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation

insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes

Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders

Physiological feedback loops apparently exist between microbes, host hormones, and immunity

The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression

studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism

We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.

Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.

Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium

L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells

the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH

Th2 cells have been shown to be activated by IL-4 and produce IL-4, IL-5, IL-10 and IL-13

Th17 cells, a more recently identified Th cell subset that has altered the classic Th1/Th2 paradigm, produce IL-17 A/F, IL-21, and IL-22. IL-1, IL-6, IL-23, and TGF-β are now known to play important roles in the differentiation and propagation of the Th17 cell lineage

there is an overall notion that pro-inflammatory Th1 and Th17 associated cytokines are elevated during the early stages of scleroderma, whereas Th2 cytokines mainly correlate with disease damage and fibrosis extent

It is noteworthy that among the many mechanisms that may mediate associations between microbiota and human health [21]–[22], pro-inflammatory and immune cell activation in colon mucosa are of great importance in relation to malignancy

B. fragilis has been shown to induce mucosal regulatory T-cell responses in the intestine involving TH17 cell recruitment in experimental models

the elevations of Bacteroides in the stool and/or IL17 immunoreactive cells in the normal mucosa appear to be promising sensitive markers