Objective To evaluate the effects and mechanisms of action of Vitamin D on human uterine leiomyoma (HuLM) cell proliferation in vitro. Design Laboratory study. Setting University hospitals. Patients(s) Not applicable. Interventions(s) Not applicable. Main Outcome Measure(s) HuLM cells were treated with 1, 25-dihydroxyvitamin D3 (Vitamin D) and cell proliferation was assayed by the MTT technique. PCNA, BCL-2, BCL-w, CDK-1 and COMT protein levels were analyzed by Western blotting. COMT mRNA and enzyme activity were assayed by quantitative RT-PCR and HPLC analysis, respectively. The role of COMT was evaluated in stable HuLM cells by silencing COMT expression. Result(s) Vitamin D inhibited the growth of HuLM cells by 47% ± 0.03 at 1 µM and by 38% ± 0.02 at 0.1 µM compared to control cells at 120 hours of treatment (P < 0.05). Vitamin D inhibited ERK activation and downregulated the expression of BCL-2, BCL-w, CDK1 and PCNA. Western blot, RT-PCR and enzyme assay of COMT demonstrated inhibitory effects of Vitamin D on COMT expression and enzyme activity. Silencing endogenous COMT expression abolished Vitamin D-mediated inhibition of HuLM cell proliferation. Conclusion(s) Vitamin D inhibits growth of HuLM cells through the down-regulation of PCNA, CDK1 and BCL-2, and suppresses COMT expression and activity in HuLM cells. Thus, hypovitaminosis D appears to be a risk factor for uterine fibroids.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease resulting in non-healing wounds affecting body areas of high hair follicle and sweat gland density. The pathogenesis of HS is not well understood but appears to involve dysbiosis-driven aberrant activation of the innate immune system leading to excessive inflammation. Marked dysregulation of antimicrobial peptides and proteins (AMPs) in HS is observed, which may contribute to this sustained inflammation. Here, we analyzed HS skin transcriptomes from previously published studies and integrated these findings through a comparative analysis with a published wound healing data set and with immunofluorescence and qPCR analysis from new HS patient samples. Among the top differently expressed genes between lesional and non-lesional HS skin were members of the S100 family as well as dermcidin , the latter known as a sweat gland-associated AMP and one of the most downregulated genes in HS lesions. Interestingly, many genes associated with sweat gland function, such as secretoglobins and aquaporin 5 , were decreased in HS lesional skin and we discovered that these genes demonstrated opposite expression profiles in healing skin. Conversely, HS lesional and wounded skin shared a common gene signature including genes encoding for S100 proteins, defensins, and genes encoding antiviral proteins. Overall, our results suggest that the pathogenesis of HS may be driven by changes in AMP expression and altered sweat gland function, and may share a similar pathology with chronic wounds.

Background: Hidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk.Objective: To provide evidence-based screening recommendations for comorbidities linked to HS.Methods: Systematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and

Proteomic analysis of murine skin has shown that a variety of heat shock proteins (HSPs) are constitutively expressed in the skin. Using murine allergic contact hypersensitivity as a model, we investigated the role of two heat shock proteins – HSP27 and HSP70 – in the induction of cutaneous cell-mediated immune responses. Immunohistochemical examination of skin specimens showed that HSP27 was present in the epidermis and HSP70 was present in both the epidermis and dermis. Inhibition of HSP27 and HSP70 produced a reduction in the DNFB contact hypersensitivity response and resulted in the induction of antigen specific unresponsiveness. Treatment of dendritic cell cultures with recombinant HSP27 caused in the upregulation of IL-1β, TNF-α, IL-6, IL-12p70 and IL-12p40 but not IL-23p19, which was inhibited when antibodies to HSP27 were added. DNFB conjugated dendritic cells that had been treated with HSP27 had an increased capacity to initiate contact hypersensitivity responses compared to control dendritic cells. This augmented capacity required TLR4 signaling because neither cytokine production by dendritic cells nor the increased induction of contact hypersensitivity responses occurred in TLR4 deficient C3H/HeJ mice. Our findings indicate that a cascade of events occurs following initial interaction of hapten with the skin that includes increased activity of heat shock proteins, their interaction with TLR4 and, in turn, increased production of cytokines that are known to enhance antigen presentation by T-cells. The results suggest that heat shock proteins form a link between adaptive and innate immunity during the early stages of contact hypersensitivity.

UVB radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, the role of innate immunity on photoimmunological processes has received little attention. The purpose of this study was to determine whether toll-like receptor-4 (TLR4) contributed to UV-induced suppression of contact hypersensitivity (CHS) responses. TLR4−/− and wild type C57BL/6 (TLR4+/+) mice were subjected to a local UVB immunosuppression regimen consisting of 100 mJ/cm2 UVB radiation followed by sensitization with the hapten DNFB. Wild type TLR4+/+ mice exhibited significant suppression of contact hypersensitivity response, whereas TLR4−/− developed significantly less suppression. The suppression in wild type TLR4+/+ mice could be adoptively transferred to naïve syngeneic recipients. Moreover, there were significantly fewer Foxp3 expressing CD4+CD25+ regulatory T-cells in the draining lymph nodes of UV-irradiated TLR4−/− mice than TLR4+/+ mice. When cytokine levels were compared in these two strains after UVB exposure, T-cells from TLR4+/+ mice produced higher levels of IL-10 and TGF-β and lower levels of IFN-γ and IL-17. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous immunosuppression.