title: Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I.
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.
  
  
  CONCLUSIONS
  Our findings strongly suggest that 5-I may be useful as a potential therapeutic agent for human rheumatoid arthritis.
authors: Division of Clinical Immunology, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo , Minato-ku, Tokyo , Japan.
authors: Noriko
authors: N
authors: Otsuki
authors: Satoshi
authors: S
authors: Iwata
authors: Taketo
authors: T
authors: Yamada
authors: Osamu
authors: O
authors: Hosono
authors: Nam H
authors: NH
authors: Dang
authors: Ryo
authors: R
authors: Hatano
authors: Kei
authors: K
authors: Ohnuma
authors: Chikao
authors: C
authors: Morimoto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D015575:Roxithromycin / Q000627:therapeutic use*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D015575:Roxithromycin; D003094:Collagen
keywords: 5-I; Collagen-induced arthritis; Monocytes; Rheumatoid arthritis; Roxithromycin; T cells