Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor –kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking. (March 2019)

• Record Type: Journal Article
• Authors: Nii, Takuro; Kuzuya, Kentaro; Kabata, Daijiro; Matsui, Toshihiro; Murata, Atsuko; Ohya, Takeshi; Matsuoka, Hidetoshi; Shimizu, Takashi; Oguro, Eri; Okita, Yasutaka; Udagawa, Chikako; Yoshimura, Maiko; Kudo-Tanaka, Eriko; Teshigawara, Satoru; Harada, Yoshinori; Yoshida, Yuji; Isoda, Kentaro; Tsuji, So-Ichiro; Ohshima, Shiro; Hashimoto, Jun; Shintani, Ayumi; Takehana, Yasuo; Tohma, Shigeto; Saeki, Yukihiko
• Is Part Of: Journal of autoimmunity. Volume 98(2019)
• Page Start: 95
• Page End: 102
• Publication Date: 2019-03
• Subjects: TNFα -- Smoking -- AhR -- NF-κB -- TNF-inhibitor -- Rheumatoid arthritis; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.12.004
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Objectives: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. Methods: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. Results: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305–3.672, P = 0.003; current/ever: 1.580, 95%CI; 0.879–2.839, P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1β and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. Conclusions: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits. Highlights: Smoking affects the efficacy of biologics differently depending on the therapeutic targets in RA. Therapeutic resistance is dominant in current-smoking RA patients with TNFi treatment. Smoke chemical components enhance both TNFα-induced NF-κB activation and cytokine production. These suggest a crosstalk between TNFα signaling and AhR signaling in the activation of NF-κB. The above crosstalk causes poor therapeutic response to TNFi in RA patients with smoking.