Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis.
Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3-signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.
Shouda
T
T
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Yoshida
T
T
Hanada
T
T
Wakioka
T
T
Oishi
M
M
Miyoshi
K
K
Komiya
S
S
Kosai
K
K
Hanakawa
Y
Y
Hashimoto
K
K
Nagata
K
K
Yoshimura
A
A
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors