Abstract
Objective: Macrolide antibiotics have immunomodulatory properties that are distinct from their antibacterial functions. We synthesized 5-I, which is a new derivative of RXM with less antimicrobial activity, and evaluated its immunomodulatory effects through both in vitro and in vivo studies.
Methods: Proliferative response, cytokine production, and expression of mRNA of T cells stimulated with anti-CD3 and anti-CD28 mAbs in the presence or absence of monocytes, cytokine production of monocytes stimulated with lipopolysaccharide, and transendothelial migration of T cells in various concentrations of 5-I were analyzed. The effect of 5-I treatment was also evaluated in a mouse model of collagen-induced arthritis.
Results: 5-I specifically inhibited production of Th1, Th17, and proinflammatory cytokines such as IL-2, IFN-γ, TNF-α, IL-6, and IL-17A. 5-I reduced the expression of RORC on CD4+ T cells, which codes for RORγt, the master regulator of Th17, and it also inhibited migration of activated T cells. Importantly, administration of 5-I to mice with collagen-induced arthritis reduced the severity of arthritis, and this effect was also observed when treatment was delayed till after the onset of disease.
Conclusion: Our findings strongly suggest that 5-I may be useful as a potential therapeutic agent for human rheumatoid arthritis.
Acknowledgement
This study was supported in part by a grant of the Ministry of Education, Science, Sports and Culture, Japan (K.O. and C.M.), a grant of the Ministry of Health, Labour, and Welfare, Japan (C.M.) and a Grant-in-Aid (E2628 and S1311011) from the Foundation of Strategic Research Projects in Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (K.O. and C.M.).
Authorship contributions
Contributions: N.O., S.I. and R.H. performed the experiments, interpreted the data, O.H. assisted with the paper, K.O. and C.M. designed the research, interpreted the data and wrote the paper, N.H.D. interpreted the data, assisted with the paper, and proofread the manuscript, and T.Y. performed the experiments, analyzed pathological results, interpreted the data and assisted with the paper.
Conflict of interest
None.