Cytokine Signaling Blockade May Suppress Rheumatoid Arthritis

January 17, 2002

NEW YORK (Reuters Health) Jan 15 - Modulation of the Janus tyrosine kinase (JAK)

STAT pathway via cytokine inducible suppressors (CIS) and suppressors of

cytokine signaling (SOCS) may be an effective way to treat rheumatoid arthritis,

according to Japanese researchers.

" Our approach, Dr. Akihiko Yoshimura of Kyushu University, Fukuoka, told Reuters

Health, " is based on the blockade of [an] intracellular signal transduction

pathway which is involved in the development of rheumatoid arthritis. " This, he

added, " may be more effective than antibody therapy against TNF-alpha or IL-6. "

This approach was suggested when Dr. Yoshimura and colleagues found that STAT3

was strongly tyrosine phosphorylated in the synovial tissue of patients with

rheumatoid arthritis, but not in those with osteoarthritis. There is evidence

that STAT3 precedes SOC3 expression and endogenous CIS3/SOCS3 " is abundantly

expressed in rheumatoid arthritis patients. "

Accordingly, the researchers injected an adenovirus carrying CIS3 DNA and

another containing dominant negative (dn) STAT3 into the ankles of mice with

antigen-induced or collagen-induced arthritis. Compared with controls, CIS3

treatment " drastically reduced the severity of arthritis and joint swelling. "

However, dnSTAT3 was less effective, particularly in the treatment of

collagen-induced arthritis.

In light of the apparent success of this approach, as well as using gene

therapy, Dr. Yoshimura continued, " we wish to find small molecules or drugs that

mimic CIS3/SOCS3 or inhibit JAK1. "

In an accompanying editorial, Dr. Rottapel of St. 's Hospital,

Toronto, Canada, calls modulation of the JAK/STAT pathway " a reasonable strategy

for new anti-inflammatory drug development, " and ventures that SOCS proteins may

be " the very brakes we should pull to control diseases of disordered cytokine

stimulation. "

J Clin Invest 2001;108:1781-1788.

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