- Paper Report
- Open Access
Neuropeptide treatment inhibits arthritis
- Cheryl Smythe1
© Biomed Central Ltd 2001
- Received: 18 September 2001
- Accepted: 2 November 2001
- Published: 2 November 2001
- Collagen-induced arthritis
- Th1/Th2 response
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38 amino acid neuropeptide belonging to the secretin-glucagon vasoactive intestinal peptide (VIP) family, which exhibits anti-inflammatory properties. PACAP has been shown to protect mice from lethal endotoxemia by decreasing proinflammatory cytokines and increasing anti-inflammatory cytokines. Furthermore, PACAP stimulates a Th2 response. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease in which the imbalance in inflammatory cytokines and T-cell responses play a key role. The authors therefore propose that PACAP may be effective in treating both the inflammatory and autoimmune conditions of RA and investigate this in an animal model of collagen-induced arthritis (CIA).
The overall incidence and severity of CIA was dramatically reduced in mice treated with PACAP 21 days after primary immunization compared to untreated controls. The joints of treated animals showed an abrogation of synoviocyte proliferation, leukocyte infiltration, pannus formation, cartilage destruction and bone erosion. Administration of PACAP 12 days after disease onset prevented further disease progression with a slight improvement of existing clinical symptoms. PACAP inhibited CIA-induced mRNA expression of the proinflammatory cytokines TNF-a, IL-6, IL-12, iNOS, IL-18, IL-1a and ?, and the chemokines monocyte chemoattractant protein-1, RANTES, MIP-1a and ? and MIP-2. In contrast levels of the anti-inflammatory cytokine IL-10 and the IL-1 receptor antagonist increased following treatment. PACAP inhibited membrane metalloproteinase-2 mRNA expression and activity. It also affected T-cell responses: T-cell clonal expansion in response to type-II collagen (CII) was partially inhibited; the CIA-induced Th1 response of high IFN-? and low IL-4 was reversed, apparently due to an increase in Th2 IL-4 secreting T cells and a decrease in Th1 IFN-? secreting T cells. Furthermore, anti-CII IgG2a levels were significantly reduced, but IgG1 levels increased in PACAP treated CIA mice and there was a decrease in the Th-suppressor ratio as a result of lower levels of CD4+ cells while CD8+ T cell numbers remained unchanged.
CIA model, histopathology, RNase protection and Northern analyses, zymography, T-cell proliferation assay, ELISA, synoviocyte culture, flow cytometry
Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP: Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease.
Nat Med 2001, 7:563-568.