Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.

Vibrio LIurnificus strain FCC, isolated from a patient with a wound infection, and reference strain ATCC 27562, were examined by electron microscopy for the presence of capsules. Both strains had a layer heavily stained with ruthenium red. The number of stained cells was high in strain FCC and low in strain ATCC 27562. The proportion of stained cells correlated with virulence against mice and with susceptibility to the bactericidal activity of normal human serum. Rapid freezing and substitution fixation, a mild method, revealed on the cell surface a fibrous layer of relatively low electron density, which we considered to represent a capsule.

Chitin concentrations greater than 0.04% (wt/wt) protected cholera vibrios against killing at low temperature. This protective effect was detected with both the soluble form of chitin, glycol chitin, and the insoluble particulate form of chitin. Some amino acids or peptides also showed the same protective effect. Vibrio cholerae is an important human diarrheal pathogen. Water contaminated with vibrios excreted from cholera patients is the main source of cholera infection. Recently, however, instances of isolation of cholera vibrios from sea or river water in nonepidemic and nontropical areas where fecal contamination has not been proved have increased (4, 6, 8, 9). Moreover, in several countries outbreaks of cholera have occurred after the consumption of imported raw seafood which had been transported in the frozen or refrigerated state (4, 5). These examples suggest that cholera vibrios

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamineindependent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ)-induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.

Sepsis is a major cause of morbidity and mortality in seriously ill patients and mitochondrial dysfunction is associated with poor outcomes in septic patients. Although interleukin-6 (IL-6) is a good prognostic marker for sepsis, the relationship between mitochondrial dysfunction and IL-6 remains poorly understood. We identified p32/C1QBP/HABP1 as a regulator of IL-6 production in response to lipopolysaccharide (LPS). LPS induced IL-6 overproduction in p32 deficient mouse embryonic fibroblasts (MEFs) through NF-κB independent but activating transcription factor (ATF) 4 dependent pathways. Short hairpin RNA-based knockdown of ATF4 in p32 deficient MEFs markedly inhibited LPS-induced IL-6 production. Furthermore, MEFs treated with chloramphenicol, an inhibitor of mitochondrial translation, produced excessive IL-6 via ATF4 pathways. Using a LPS-induced endotoxin shock model, mice with p32 ablation in myeloid cells showed increased lethality and overproduction of IL-6. Thus, this study provides a molecular link how mitochondrial dysfunction leads to IL-6 overproduction and poor prognosis of sepsis.

The protective effect of heat-killed Lactobacillus casei YIT9018 (LC 9018) against Pseudomonas aeruginosa infection in mice was compared with that of Corynebacterium parvum. Survival of mice after intraperitoneal (i.p.) infection with P. aeruginosa was augmented in mice that had been pretreated i.p. with LC 9018 5 days previously. Similar treatment of mice with C. parvum, however, was not effective at all. Moreover, mice became more susceptible to infection with P. aeruginosa after such treatment. Growth of P. aeruginosa in the peritoneal cavity and spleen was markedly inhibited in LC 9018-pretreated mice, whereas such inhibition of bacterial growth was not observed in C. parvum-treated mice. The protective effect of LC 9018 was observed in mice subjected to 800 rads of whole body irradiation but was abrogated when mice were treated with carrageenan. These results suggest that augmentation of the resistance of mice to P. aeruginosa was caused by the induction of activated macrophages. The number of macrophages detectable in the peritoneal cavity was almost the same in LC 9018-and C. parvum-treated mice. Growth of Listeria monocytogenes was inhibited by pretreatment with LC 9018. Inhibition of L. monocytogenes was also observed after the same pretreatment with C. parvum. It was suggested that macrophages activated with LC 9018 were involved in the protective immunity to P. aeruginosa.

Introduction: Recently, the sodium-glucose cotransporter2 (SGLT2) inhibitor empagliflozin has been shown to lower cardiovascular risk among diabetic patients. It is intriguing that some SGLT2 inhibitors have been found to increase low-density lipoprotein (LDL) cholesterol levels, while the relevance to high-density lipoprotein (HDL) cholesterol is unknown. Although the inhibitory effect of SGLT2 inhibitors on glucose reabsorption may accelerate compensatory lipid metabolism and subsequently reduce body weight and affect the lipid profile, much remains unclear about this mechanism. Therefore, we conducted this study to investigate in detail how canagliflozin affects lipoprotein fractions including LDL and HDL subclasses. Materials and Methods: This study is a multicenter prospective study. The participants were patients with 22 type 2 diabetes (60.7 ± 11.6 years, 59.1% of men) who had HbA1c ⩾ 7.0% and consented to participate in the study. They were administered 100 mg canagliflozin orally once per day. Biochemistry test and cholesterol levels of 20 lipoprotein fractions (G1-G20) using high performance liquid chromatography methods were examined before and after 12 weeks of treatment period. Results: Significant decreases were observed in the participants’ body weight (69.7 to 67.9 kg, P < .001), systolic blood pressure (129.3 to 119.5 mm Hg, P < .01), and HbA1c (8.5% to 7.4%, P < .001). Cholesterol levels in the 20 lipoprotein fractions increased for very large HDL (G14, G15) and large HDL (G16) ( P < .05). Conclusions: Reduction in body weight, improvement of blood glucose levels, and increases in very large HDL and large HDL subclasses were observed after canagliflozin treatment. These beneficial changes might contribute to subsequent suppression of cardiovascular outcomes.

Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood. Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4. Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1. Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.