Abstract
IntroductionTumor necrosis factor-alpha (TNFα) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFα antagonists in RA is poorly defined. Immunization of DBA/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFα antagonists, suggesting similar etiology to RA. In this study, we explored TNFα-related mechanisms of arthritis.MethodsFirst, we performed GeneChip analysis using splenocytes of mice with GPI-induced arthritis. Expression of TNFα-induced adipose-related protein (TIARP) mRNA and protein in spleens, joints and lymph nodes was evaluated, and fluctuation of TIARP mRNA was analyzed after administration of anti-TNFα monoclonal antibody (mAb). Localization of TIARP in spleen and joints was also explored. Six-transmembrane epithelial antigen of the prostate (STEAP) families of proteins, the human ortholog of TIARP gene, were also evaluated in human peripheral blood mononucleocytes and synovium.ResultsAmong the arrayed TNFα-related genes, the expression of TIARP mRNA was the highest (more than 20 times the control). TIARP mRNA was detected specifically in joints and spleens of arthritic mice, and their levels in the synovia correlated with severity of joint swelling. Treatment with anti-TNF mAb significantly reduced TIARP mRNA expression in splenocytes. Among the splenocytes, CD11b+ cells were the main source of TIARP mRNA. Immunohistochemistry showed that TIARP protein was mainly localized in hyperplastic synovium. Among the STEAP family of proteins, STEAP4 was highly upregulated in joints of patients with RA and especially co-localized with CD68+ macrophages.ConclusionsThe results shed light on the new mechanism of action of TNFα antagonists in autoimmune arthritis, suggesting that TIARP plays an important role in inflammatory arthritis, through the regulation of inflammatory cytokines.
Highlights
Tumor necrosis factor-alpha (TNFα) plays a pivotal role in rheumatoid arthritis (RA); the mechanism of action of TNFα antagonists in RA is poorly defined
We identified that anti-interleukin-6 (IL-6) receptor monoclonal antibody (mAb) blocks the development of glucose-6-phosphate isomerase (GPI)-induced arthritis [3,4]
Arthritis was documented at day 8, and severe arthritis was recorded at day 14, with ankle swelling reaching a maximum at day 14 but subsiding gradually on follow-up
Summary
Tumor necrosis factor-alpha (TNFα) plays a pivotal role in rheumatoid arthritis (RA); the mechanism of action of TNFα antagonists in RA is poorly defined. [2] reported that continuous injections of human TNF receptor (TNFR) p75-IgG-Fc fusion protein (Etanercept) from days 0 to 9 completely protected against the development of arthritis in glucose-6-phosphate isomerase (GPI)-induced arthritis. In this regard, we recently demonstrated a clear therapeutic effect of anti-TNF monoclonal antibody (mAb) in mice with GPIinduced arthritis, and the therapeutic response correlated with the in vitro regulation of TNF production [3]. We identified that anti-interleukin-6 (IL-6) receptor mAb blocks the development of GPI-induced arthritis [3,4] These results indicate that the GPI-induced arthritis model is suitable for studying the mechanisms of action of TNFα antagonists as well as IL-6 antagonists in RA patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
