T-cells & Stem cells

Benjamin Button wrote:Yes smurfy, I agree, perhaps people are just jaded and can't discern between irrelevant discoveries and very relevant ones like this one..

Insulin-like growth factor-1 induces regulatory T cell-mediated suppression of allergic contact dermatitis in mice

Allergic contact dermatitis (ACD) is triggered by an aberrant hyperinflammatory immune response to innocuous chemical compounds and ranks as the world’s most prevalent occupational skin condition. Although a variety of immune effector cells are activated during ACD, regulatory T (Treg) cells are crucial in controlling the resulting inflammation. Insulin-like growth factor-1 (IGF-1) regulates cell proliferation and differentiation and accelerates wound healing and regeneration in several organs including the skin. Recently IGF-1 has also been implicated in protection from autoimmune inflammation by expansion of Treg cells. Here, we demonstrate that ectopic expression of IGF-1 in mouse skin suppresses ACD in a Treg cell-specific manner, increasing the number of Foxp3+ Treg cells in the affected area and stimulating lymphocyte production of the anti-inflammatory cytokine interleukin 10. Similar therapeutic effects can be achieved with systemic or topical delivery of IGF-1, implicating this growth factor as a promising new therapeutic option for the treatment of ACD.

Gender And Sex Hormones Influence CD4 Regulatory T Cells And Their Expression Of FoxP3 In Healthy People And In SLE.

Purpose:
The goal of the present study was to determine the role of gender and the effect of sex hormones on the regulation of Foxp3 gene in healthy individuals and in SLE patients.
Methods:
Levels of sex hormones (17 b-estradiol, testosterone), cytokines, and chemokines were measured by ELISA in the serum/plasma of healthy donors and from the culture supernatant of peripheral blood mononuclear cells (PBMC) isolated from SLE patients and healthy controls. PBMC were immunophenotyped by flow cytometry, and mRNA gene expression studies were performed by real time PCR. Protein expression was analyzed by intracellular staining and by Western blot analysis. The in vitro effect of sex hormones 17 b-estradiol (60–100, 500pg/ml), and testosterone (100pg/ml) were studied by culturing sorted CD4+CD25hiCD127lo regulatory T cells for 24–72 hours followed by FACS/Western blot analyses.
Results:
1- The numbers of CD4+ CD25hi Foxp3+ and of CD8+ FoxP3+ regulatory T cells are significantly decreased in healthy females compared to healthy males (p<0.01).
2- Both CD4+CD25+hi and CD8+CD25+ subsets of healthy males had 3–4-fold higher Foxp3 mRNA compared to healthy females.
3- Plasma 17b-estradiol levels are significantly increased in female SLE patients compared to healthy females (p<0.01).
4- The addition of 17 b- estradiol (physiologic cycling luteal phase concentrations of 60 pg/ml) for 24 hours to cultured PBMC from healthy women (but not men) increased the total numbers of cells expressing CD4, CD25 and FoxP3. These effects were not seen in cells in women with SLE.
5- Incubation of CD4+ regulatory T cells with 100 pg/ml of 17b- estradiol maintained FoxP3 expression in SLE women, in contrast to the usual increase in CD4+ Treg that occurs in healthy women at this concentration.
6- Testosterone (100 pg/ml) significantly increased FoxP3 expression in CD4+CD25hi cells from women with SLE. In fact, plasma concentrations of testosterone in those women correlated positively with the expression of FoxP3 in their CD4+CD25+ T cells (p <0.04).
Conclusions:
Women may be more susceptible than men to SLE and other autoimmune diseases in part because many healthy women have fewer regulatory T cells and less FoxP3 expression in those cells. In addition, women with SLE, compared to healthy women, seem to have less ability to generate CD4+ Treg in response to physiologic concentrations of 17 b- estradiol, whereas the testosterone metabolite increases the generation of Tregs. These data suggest that gender and sex hormones may influence susceptibility to SLE via their effects on regulatory T cells.

Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae.

We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6h after CGRP administration. DHT administration for 3weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice.

Insulin-like growth factor-1 induces regulatory T cell-mediated suppression of allergic contact dermatitis in mice

Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects.

IGF-I alters lymphocyte survival and regeneration in thymus and spleen after dexamethasone treatment.

Insulin-like growth factor I (IGF-I) is a growth factor for the immune system, increasing lymphocyte number and function via greater lymphocyte generation and/or survival. We investigated the effects of IGF-I on lymphocyte survival and regeneration in the thymus and spleen after dexamethasone (Dex) treatment in rats maintained with parenteral nutrition and given recombinant human IGF-I (800 micrograms/day) for 12 h, 48 h, and 5 days. IGF-I did not prevent Dex-induced apoptosis of thymocytes but reduced cell death in the spleen at 12 and 48 h. IGF-I exerted a modest protective effect (10-15% reduction in cell loss) on all splenic T and B cell subsets examined by flow cytometry. IGF-I enhanced recovery of CD4+8+ immature T cells in the thymus and decreased the proportion of CD8+ (cytotoxic/suppressor) T cells in the spleen. In rats not treated with Dex, IGF-I significantly increased total lymphocyte number and the number of CD4+8+ T cells in thymus and spleen. Our results suggest that IGF-I may alter homeostasis in the immune system by modulating lymphocyte generation and survival.

Role of systemic and local IGF-I in the effects of estrogen on growth and epithelial proliferation of mouse uterus.

IGF-I is a critical regulator of uterine growth, and locally produced uterine IGF-I could mediate the effects of 17beta-E2 on growth and cellular proliferation. We used IGF-I knockout (KO) mice and tissue grafting to determine the roles of local and systemic IGF-I in uterine growth and E2 responsiveness. Uteri from adult KO mice and neonatal and adult wild-type (WT) mice were grown under the renal capsule of female athymic mice for 4 wk. Initial uterine weights of adult KO and neonatal WT mice were 5% or less of those of adult WT uteri. Weights of adult WT uterine grafts did not increase during grafting. Weights of adult KO and neonatal WT uteri exposed to normal systemic levels of IGF-I in athymic hosts increased 20- to 30-fold to equal or exceed those of adult WT grafts. Uterine epithelial height, reduced in KO mice, was restored to WT levels in KO uteri grafted into athymic hosts. The absence of local IGF-I production in KO uteri did not impair E2- induced epithelial proliferation in KO uterine grafts. Neonatal WT uteri grafted into KO hosts showed minimal growth, providing evidence that local uterine IGF-I production is insufficient to support uterine growth in the absence of systemic IGF-I. E2 treatment of KO females produced minimal uterine growth, confirming that lack of IGF-I, rather than E2, caused the uterine hypoplasia. In summary, systemic IGF-I supports normal uterine growth and E2 response in the absence of local IGF-I. Local IGF-I is not a direct mediator of E2 action in uterus, and systemic IGF-I may be more important than previously thought for growth of the uterus and other tissues.