Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A New Derivative of Roxithromycin Modulates Immunological Responses and Ameliorates Collagen-Induced Arthritis.
Otsuki1, Noriko, Iwata1, Satoshi, Kumagai1, Emi, Yamada2, Taketo, Katayose1, Tomoki, Kichikawa1, Yoshiko, Hosono1, Osamu
Macrolide antibiotics have many biological activities distinctly different from antibacterial functions. Previously we showed that Roxithromycin (RXM), a macrolide antibiotic with a 14-member macrocyclin ring, inhibited in vitro production of proinflammatory cytokines such as TNF-a and IL-6 by T cells and macrophages. More interestingly, oral administration of RXM in mice with collagen-induced arthritis (CIA) reduced the severity of arthritis and serum level of IL-6 as well as leukocyte migration into the affected joints and destruction of bones and cartilages. In the present study, we synthesized the new derivertive of RXM named 5-I with less antimicrobial activity and studied the immunomodulatory effects of 5-I both in vitro and in vivo.
Proliferative response and cytokine production by human PBMCs and T cells stimulated with anti-CD3 plus anti-CD28 mAbs, cytokine production by human monocytes stimulated with lipopolysaccharide, and transendothelial migration of human T cells were analyzed in the presence or absence of various concentration of 5-I and RXM. In addition, 5-I and RXM-mediated alteration of mRNA expressions were evaluated by cDNA microarray anaysis and RT-PCR using human CD4+ T cells. The in vivo effect of the oral administration of 5-I or RXM was evaluated using collagen-induced arthritis model mice (DBA/1J strain) by scoring of arthritis and pathological examination.
5-I did not affect the proliferation of lymphocytes and the production of Th2-type cytokines, whereas it specifically inhibited production of Th1, Th17, and proinflammatory cytokines, such as IL-2, IFN-g, TNF-a, IL-6, and IL-17A by human T cells and/or monocytes. Microarray analysis revealed that 5-I reduced the expression of RORgt which is the master regulator of Th17. 5-I also inhibited the activated T cells migration. We found that the administration of 5-I to collagens-induced arthritis mice reduced the severity of the desease in the comparable level to RXM. The effectiveness was also observed in the delayed administration after onset of the disease, suggesting 5-I may be useful in the treatment of CIA as well as its prevention.
Our findings strongly suggest that 5-I is a promising low molecular compounds for the possible clinical application in the treatment of rheumatoid arthritis in human. Furthermore, 5-I may be a useful lead compound to regulate the differentiation of Th17 population.
To cite this abstract, please use the following information:
Otsuki, Noriko, Iwata, Satoshi, Kumagai, Emi, Yamada, Taketo, Katayose, Tomoki, Kichikawa, Yoshiko, et al; A New Derivative of Roxithromycin Modulates Immunological Responses and Ameliorates Collagen-Induced Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1137