Nicotine‐induced differential modulation of autoimmune arthritis in the Lewis rat involves changes in interleukin‐17 and anti–cyclic citrullinated peptide antibodies

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disease, and smoking is an important environmental factor in a subset of RA patients. A role of the cholinergic antiinflammatory pathway in autoimmune inflammation is increasingly being realized. Nicotine is a major component of cigarette smoke, and it stimulates the α7 nicotinic acetylcholine receptors. Therefore, defining the mechanisms underlying the immunomodulatory effects of nicotine on arthritis is of high relevance. The purpose of this study was to address this issue using the rat adjuvant-induced arthritis (AIA) model of human RA. Lewis rats were immunized subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra for disease induction. Rats were treated with nicotine intraperitoneally either before (pretreatment) or after (posttreatment) the onset of AIA. Control rats received the vehicle (buffer) in place of nicotine. The severity of arthritis was assessed and graded. The draining lymph node cells were tested for T cell proliferative and cytokine responses against the disease-related antigen mycobacterial heat-shock protein 65. The sera were tested for anti-cyclic citrullinated peptide (anti-CCP) antibodies and anti-mycobacterial Hsp65 antibodies. Nicotine pretreatment aggravated the arthritis, whereas nicotine posttreatment suppressed the disease. This altered severity of AIA directly correlated with the levels of the anti-CCP antibodies, of the Th1/Th17 cytokines, and of the corresponding dendritic cell-derived cytokines. The majority of these effects on cellular responses could be replicated in vitro. Nicotine-induced modulation of AIA involves specific alterations in the disease-related cellular and humoral immune responses in AIA. These results are of significance in advancing our understanding of the pathogenesis of RA.