Rheumatoid Arthritis: Wei X

Luo X, Zuo X, Zhang B, Song L, Wei X, Zhou Y, Xiao X. · Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, China. · Cell Stress Chaperones. · Pubmed #18392950 links to  free full text

Abstract: It has recently been suggested that heat shock protein (Hsp) 70, an intracellular protein, can be released into the extracellular compartment and exert important immunomodulatory functions. Although elevated Hsp70 has been found in synovial fluid from patients with rheumatoid arthritis (RA), its sources and extracellular functions remain unclear. In this study, we explored whether stress response such as heat stress or exposure to tumor necrosis factor-alpha (TNF-alpha) could induce Hsp70 release from RA fibroblast-like synoviocytes (FLSs) and whether extracellular Hsp70 would stimulate cytokine production in RA FLSs. Cultured FLSs were obtained from patients with RA. The expression of intracellular Hsp70 was studied by Western blot. Hsp70 release and the production of interleukin (IL)-6, IL-8, and IL-10 by RA FLSs were studied by specific enzyme-linked immunosorbent assays. The levels of Toll-like receptor (TLR) 2 and 4 mRNA and protein in FLSs were analyzed using reverse transcription-polymerase chain reaction and Western blotting. Treatment with sublethal heat shock or TNF-alpha results in the up-regulation of intracellular Hsp70 in FLSs and Hsp70 release from RA FLSs. In vitro studies show that extracellular Hsp70 can induce anti-inflammatory cytokine IL-10 production in FLSs. The mRNA and protein expression of TLR2 and TLR4 was demonstrated in FLSs, and TLR4 blocking abrogated the up-regulatory effects of Hsp70 on IL-10 production. Thus, these results lend support to the hypothesis that Hsp70 is actively released from FLSs in response to heat shock or TNF-alpha and Hsp70 may be a major paracrine/autocrine inducer of IL-10 production in FLSs via TLR4.

Niedbala W, Cai B, Wei X, Patakas A, Leung BP, McInnes IB, Liew FY. · Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK. · Ann Rheum Dis. · Pubmed #18199596 No free full text.

Abstract: OBJECTIVE: To investigate the potential role of interleukin (IL) 27 in rheumatoid arthritis (RA) by examining the expression of IL27 in the articular joints of patients with RA and the effect of recombinant IL27 in vivo in a murine model of collagen-induced arthritis (CIA). METHODS: Synovial membranes from patients with RA were examined for the presence of IL27 by immunohistochemistry and by western blot. Mice developing CIA were treated with IL27 and the ensuing disease progression and immunological profile determined. The effect of IL27 on T-cell response in vitro was also ascertained. RESULTS: IL27 was clearly detected in the RA synovial membranes. Short-term administration of IL27 at the onset of the disease significantly attenuated disease severity compared with untreated controls. Histological examination showed that while untreated mice developed severe cellular infiltration in the joints, synovial hyperplasia and joint erosion, this pathology was profoundly reduced in IL27-treated animals. Treatment of mice with IL27 also decreased the amounts of serum IL6 and collagen-specific IgG2a. Spleen and lymph node cells from the IL27-treated mice produced significantly less interferon gamma and IL17 than cells from the control mice when cultured with collagen in vitro. CONCLUSION: These results demonstrate that IL27 may be a potential therapeutic agent against RA at the onset of the disease.

Verri WA, Cunha TM, Ferreira SH, Wei X, Leung BP, Fraser A, McInnes IB, Liew FY, Cunha FQ. · Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. · Eur J Immunol. · Pubmed #17979156 No free full text.

Abstract: We have investigated the mechanisms underlying IL-15-induced neutrophil migration into inflamed tissues. IL-15 induced neutrophil migration to the peritoneal cavity in mice in a time- and dose-dependent manner. The cell migration was not induced in IL-18-/-, MIP-1alpha (CCL3)-/-, TNFR1-/- or 5-LOX-/- mice but was normal in IFN-gamma-/- mice. IL-15-induced neutrophil migration was inhibited by anti-MIP-2 (CXCL2) antibody or MK886 (leukotriene synthesis inhibitor). IL-18-induced neutrophil migration was also dependent on TNFR1, MIP-1alpha, MIP-2 and leukotriene. Consistent with this observation, IL-15 induced IL-18 production, and IL-15 or IL-18 injection induced the production of MIP-2, MIP-1alpha, TNF-alpha and LTB4. In an antigen-specific inflammation model, ovalbumin (OVA)-induced neutrophil migration was completely inhibited by soluble IL-15Ralpha (sIL-15Ralpha) or anti-MIP-2 antibody. Furthermore, cell migration was absent in IL-18-/-, MIP-1alpha-/-, TNFR1-/-, or 5-LOX-/- mice. OVA challenge induced the release of MIP-2, MIP-1alpha, TNF-alpha and LTB4 in the peritoneal cavity in an IL-15- and IL-18-dependent manner. We also found that neutrophils from the peripheral blood and synovial fluid of patients with rheumatoid arthritis produced substantial amounts of IL-18 and LTB4 following activation by IL-15. Together, these results demonstrate that IL-15 plays an important role in antigen-induced neutrophil migration during inflammation, triggering a sequential OVA, IL-15, IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB4 and neutrophil migration signaling cascade.

Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P, Lin C, Fiebiger E, Wei X, Wu Y, Hicklin D, Bohlen P, Detmar M. · Cutaneous Biology Research Center, Massachusetts General Hospital, Bldg 149, 13th St, Charlestown, MA 02129, USA. · Blood. · Pubmed #15100155 links to  free full text

Abstract: Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy.

Jiang HR, Wei X, Niedbala W, Lumsden L, Liew FY, Forrester JV. · Department of Ophthalmology, University of Aberdeen Medical School Foresterhill, Aberdeen, United Kingdom. · Invest Ophthalmol Vis Sci. · Pubmed #11133864 links to  free full text

Abstract: PURPOSE: Interleukin (IL)-18 has been described as a proinflammatory cytokine in rheumatoid arthritis and bacterial infectious diseases. The present study was designed to determine the role of IL-18 in a model of ocular experimental autoimmune uveitis (EAU). The initial studies were conducted to detect the expression of IL-18 in normal mouse eye tissue, and the later studies investigated induction of EAU in mice with an IL-18(-/-) phenotype. METHODS: IL-18 detection was performed by using 5-bromo-4-chloro-3-indoyl-ss--D-galactopyranoside (X-Gal) staining on frozen sections of eyes from mice (129/CD1, DBA1, and Balb/c), either of normal phenotype (+/+) or of deficiency (+/-, -/-) in the IL-18 gene which had been replaced by introduced genes including LacZ under the control of an IL-18 promotor. Severity of EAU was assessed in DBA1 and 129/CD1 wild-type (WT) or IL-18 knockout (KO) mice after immunization with the uveitogenic antigen: interphotoreceptor retinal binding protein (IRBP) peptide 161-180. Lymphocyte proliferation and cytokine production were also measured in WT and IL-18 KO DBA1 mice 15 days after immunization. RESULTS: IL-18 is constitutively expressed in the epithelial cells in iris, ciliary body, and retina. EAU-resistant mice (129/CD1) with an IL-18(-/-) phenotype remained resistant after immunization with IRBP peptide (P161-180). However, EAU-susceptible mice (DBA1) exhibited disease with similar histologic characteristics, despite a generalized reduction of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha on an IL-18(-/-) phenotype. DBA1 IL-18(-/-) also demonstrated reduced IL-10 production. CONCLUSIONS: The IL-18 gene is not necessary for the initiation or pathogenesis of EAU induced by IRBP peptide 161-180. IL-18 is expressed in the epithelial cells in iris, ciliary body, and retina in the eyes, but its role in the eye remains undetermined.