IL-36α from Skin-Resident Cells Plays an Important Role in the Pathogenesis of Imiquimod-Induced Psoriasiform Dermatitis by Forming a Local Autoamplification Loop.

IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36ß), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1ß, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1ß, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.

Fecal microbiota transplantation prevents Candida albicans from colonizing the gastrointestinal tract.

Gut microbes symbiotically colonize the gastrointestinal (GI) tract, interacting with each other and their host to maintain GI tract homeostasis. Recent reports have shown that gut microbes help protect the gut from colonization by pathogenic microbes. Here, we report that commensal microbes prevent colonization of the GI tract by the pathogenic fungus, Candida albicans. Wild-type specific pathogen-free (SPF) mice are resistant to C. albicans colonization of the GI tract. However, administering certain antibiotics to SPF mice enables C. albicans colonization. Quantitative kinetics of commensal bacteria are inversely correlated with the number of C. albicans in the gut. Here, we provide further evidence that transplantation of fecal microbiota is effective in preventing Candida colonization of the GI tract. These data demonstrate the importance of commensal bacteria as a barrier for the GI tract surface and highlight the potential clinical applications of commensal bacteria in preventing pathogenic fungal infections.

IL-1R2 deficiency suppresses dextran sodium sulfate-induced colitis in mice via regulation of microbiota.

Ulcerative colitis (UC) is an inflammatory disease of the colon. IL1R2, which encodes IL-1 receptor type 2 (IL-1R2), was reported as a risk gene for UC. To elucidate the roles of IL-1R2 in the development of colitis, we examined the development of dextran sodium sulfate-induced colitis, a mouse model for UC using Il1r2-/- mice. We found the severity score of colitis was milder in Il1r2-/- mice compared with wild-type (WT) mice when they were housed separately, however the severity score was similar when they were housed in a cage. In the separate housing condition, relative contents of Actinobacteria and Bacilli in feces of Il1r2-/- mice were lower than that of WT mice. Furthermore, IL-1ß induced the expression of antimicrobial peptides (AMPs) from colon. Thus, we show that IL-1R2 is harmful for the development of colitis, because IL-1R2 promotes the growth of proinflammatory intestinal microbiota by suppressing IL-1ß-induced AMP production.

[Effects of raloxifene on bone biomarkers in postmenopausal women on maintenance haemodialysis].

Postmenopausal women on maintenance haemodialysis (MHD) has considerably higher risk of bone fracture than general population with combination of postmenopausal osteoporosis and renal osteodystrophy. However, the treatment of osteoporosis on MHD has not been established. Evidence indicates raloxifene (RLX), a selective estrogen receptor modulator, is effective for a protection of bone fracture without increasing of breast cancer and endometrial cancer. We hereby report short-term use experience of RLX for the postmenopausal MHD patients. Fifteen postmenopausal MHD patients with less than 80% of YAM bone density in DEXA administrated 60 mg RLX on every HD days (3 days/week). Serum NTX level significantly decreased after 6 months (180 +/- 18 vs. 95 +/- 12 nmol/BCE/L, p< 0.05), however, i-PTH did not have the significant difference. (115 +/- 23 vs. 157 +/- 29 pg/mL). RLX is effective for bone biomarker improvement in postmenopausal MHD patients. Further evaluation for the effectiveness and safety of RLX is necessary in the long term.

Early effects of parathyroidectomy on erythropoietin production in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2-HPT) has an adverse effect on renal anemia and may cause a hyporesponsiveness to recombinant human erythropoietin (rHuEpo) in patients with chronic renal failure. The early effects of parathyroidectomy (PTx) on renal anemia, erythropoietin production, and nutritional state were examined. METHODS: Twenty-nine patients under hemodialysis therapy received a PTx for 2-HPT. They were prospectively studied regarding hematological parameters, rHuEpo use, plasma erythropoietin levels, and nutritional condition until 12 months after PTx. RESULTS: The hemoglobin level showed a significant increase from 3 months after PTx (10.2% +/- 1.5% to 11.2% +/- 1.3%; P <0.01), associated with a consistent increase of the reticulocyte count. These changes lasted until 12 months after PTx. The plasma erythropoietin level showed a gradual increase of up to about 5 times the level of the preoperative value, until 12 months after PTx (22.6 +/- 10.1 to 106.3 +/- 112.1 mU/mL; P <0.001). The weekly dose of rHuEpo administration decreased after 3 months. The serum levels of albumin and total protein also significantly and gradually improved until 12 months after PTx. CONCLUSIONS: PTx caused a significant early improvement in renal anemia in patients with secondary hyperparathyroidism. This effect may be caused by an enhanced erythropoietin production and may also be partially due to the improved nutritional state after PTx.

Impaired taste acuity in patients with diabetes mellitus on maintenance hemodialysis.

AIMS: It has been reported that taste acuity for the four primary tastes, sour, sweet, salty and bitter, is impaired in hemodialysis (HD) patients. However, there have been no studies reported on taste acuity of diabetic HD patients. The present study aimed to quantify and compare the taste acuity of diabetic and non-diabetic HD patients, and further to determine if there were correlations between diminished taste acuity and certain blood serum parameters typically askew in hemodialysis patients. METHODS: In a test group of 24 diabetic and 24 non-diabetic HD patients matched for age, body mass index and duration of HD, taste acuity for the four tastes was determined by asking patients to identify them at varying concentrations. RESULTS: Statistical analyses indicate that bitter and total taste acuity were significantly impaired in diabetic HD patients. In diabetic HD patients, correlation was found between sweet, salty or total taste acuity and blood urea nitrogen or normalized protein catabolic rate. CONCLUSIONS: We conclude that taste acuity is partially impaired in diabetic HD patients, and suggest this contributes to reduced appetite, leading to malnutrition and poor prognoses.