IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

Dysregulated host/microbial interactions play a pivotal role in the pathogenesis of inflammatory bowel disease. We previously reported that chitinase 3-like-1 (CHI3L1) enhances bacterial adhesion and invasion on/into colonic epithelial cells (CECs). In this study, we designed to identify the exact mechanism of how CHI3L1 enhances the bacterial adhesion on CECs in vitro. As compared with wild type (WT) of Serratia marcescens, chitin binding protein (CBP) 21 knockout strain of S. marcescens significantly decreased the adhesion to SW480 cells that express CHI3L1 endogenously. A CBP21 fusion protein was produced with CBP21-expressing vector, which was transformed into BL21 strain of Escherichia coli. CBP21 overexpression significantly increased the adhesion, but not invasion, of nonpathogenic E. coli. The adhesion of S. marcescens and CBP21-overexpressing E. coli was inhibited by coculture with chitin, but not with other carbohydrates. After overexpressing CHI3L1 on SW480 cells, the adhesion rate of CBP21-overexpressing E. coli was further increased by approximately twofold. Genetically engineered E. coli with a single mutation of either Thy-54 or Glu-55 position of CBP21 exhibited a decreased binding ability, and the binding was 74% diminished by the combined mutations of three amino acids (Thy-54, Glu-55 and Glu-60) as compared with WT. Inhibition of CHI3L1 by anti-CHI3L1 antibody or CHI3L1-specific short interfering RNA reduced the adhesion of CBP21-overexpressing E. coli to CECs. In conclusion, CHI3L1 is involved in the enhancement of CBP-expressing bacterial adhesion to CECs. CBP21 and its homologs may be required for the CHI3L1-mediated enhancement of bacterial adhesion to CECs through the conserved amino-acid residues.

IL-10 is an immunosuppressive cytokine. Although previous studies have reported that exogenous delivery of IL-10 reduced airway inflammation in experimental allergic airway inflammation, the mechanism of action has not been fully clarified. In this report, we elucidated a mechanism of action of IL-10 in vivo. BALB/c mice were immunized and aerosol challenged with OVA-Ag. We delivered the IL-10 gene to the mice before systemic sensitization or during aerosol Ag challenge by administering an IL-10-producing plasmid vector. Not only presensitization delivery of IL-10, as reported, but also delivery during inflammation strongly suppressed the development of airway eosinophilia and hyperreactivity. Presensitization delivery suppressed the Ag-specific Th2-type immune response in both the lung and spleen. In contrast, delivery in the effector phase suppressed the Th2 response only in the lung, whereas that in the spleen was not affected. IL-10 gene delivery did not induce the development of a regulatory phenotype of T cells or dendritic cells; rather, it suppressed the overall functions of CD11c+ APCs of the lung such as Ag-presenting capacity, cytokine production, and transportation of OVA-Ag to lymph nodes, thus attenuating Th2-mediated allergic airway inflammation. Further, IL-10 revealed a distinct immunosuppressive effect in the presence of Ag and APCs. These results suggest that suppression of APC function in the lung, the site of immune response, played a critical role in the IL-10-mediated suppression of Ag-induced airway inflammation and hyperreactivity. Therefore, if delivered selectively, IL-10 could site specifically suppress the Ag-specific immune response without affecting systemic immune responses.

Objective: To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease-modifying antirheumatic drugs (DMARDs). Methods:We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July 2010 to December 2012. Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were retrieved from the medical records.Results: During the study period, 251 patients were administered various biological DMARDs. Six patients with a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study. Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a median of 18 months (range: 2-27 months) and HBV-DNA was examined a median of seven times (range: 2-27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving etanercept. However, HBV-DNA levels were below the quantitation limit (<2.1 log copies mL À1 ) in all three patients. HBV-DNA became negative again within several months in all three patients, while biological DMARDs were continued and liver function tests remained normal throughout.Conclusion: HBV-DNA reactivation occurred in 5.3% of RA patients with prior HBV infection during treatment with biological DMARDs, but there were no associated clinical manifestations. Accordingly, it seems that biological DMARDs can be used safely in patients with RA.

Objective. The renin-angiotensin system plays an important role in the regulation of cardiovascular, renal, and endocrine functions. Recent studies have demonstrated that angiotensin II has proinflammatory effects that may contribute to the pathogenesis of immune-mediated diseases. We used the collageninduced arthritis (CIA) model to investigate the influence of angiotensin II receptor blockers (ARBs) on antigen-specific immune responses and determine whether ARBs have preventive or therapeutic effects on the development of arthritis.Methods. We administered ARBs (olmesartan, candesartan, and telmisartan) to mice and evaluated antigen-specific T cell proliferation and cytokine production following immunization with ovalbumin (OVA) or type II collagen in Freund's complete adjuvant (CFA) or aluminum hydroxide (alum). Next, we induced CIA in DBA/1 mice and administered olmesartan. The severity and incidence of arthritis were scored according to clinical manifestations, and joint tissue sections were examined histopathologically.Results. ARBs severely suppressed lymphocyte proliferation and interferon-␥ production in mice immunized with OVA or type II collagen in CFA. Olmesartan also suppressed lymphocyte proliferation in mice immunized with ovalbumin in alum. In the CIA model, olmesartan reduced the mean arthritis score and the incidence of severe arthritis, even when it was administered only after disease onset. Histopathologic findings for joint destruction were improved in olmesartantreated mice.Conclusion. ARBs suppressed antigen-specific immune responses for Th1 and Th2 in vivo. Furthermore, olmesartan suppressed the development of severe arthritis and joint destruction in the CIA model. These findings suggest that ARBs may have therapeutic potential in rheumatoid arthritis.The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and fluid homeostasis. Two distinct subclasses of the angiotensin II (Ang II) receptors, AT 1 and AT 2 , have been described (1,2). Ang II, the major biologically active peptide produced by the RAS, causes cell proliferation and fibrosis via the AT 1 receptor and is a factor in various diseases such as hypertension, glomerular disease, and congestive heart failure (3,4).Emerging evidence suggests that the RAS, in addition to promoting cell growth and proliferation, may also have potent proinflammatory effects that contribute to disease pathogenesis. For example, Shao et al (5) showed that levels of the Th1 cytokine interferon-␥ (IFN␥) increased and those of the Th2 cytokine interleukin-4 (IL-4) decreased in Ang II-infused hypertensive rats with kidney injury, and that the administration of olmesartan, an Ang II receptor blocker (ARB), corrected this imbalance of Th subsets. showed that Ang II activated NF-B and up-regulated NF-B-related genes both in vivo and in vitro.Moreover, several recent studies demonstrated the protective effect of RAS antagonists in immunologically mediated diseases. For example, some groups of investigators demonstrated t...