Cytokines and Acute Phase Proteins in Rheumatoid Arthritis

Cytokines are extracellular signalling glycoproteins that play an important pathological role in rheumatoid arthritis (RA) where they mediate acute inflammation, chronic inflammation and connective tissue destruction. In RA the macrophage-derived cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor (TNF), colony stimulating factors (CSFs) and growth factors play a key role in amplifying and perpetuating inflammation. IL-1 and TNF activate cartilage and bone degrading enzymes, while IL-8 recruits inflammatory cells into the joint. IL-1 and TNF play an important role in the acute phase response in that they potently induce IL-6, itself the major mediator and regulator of hepatic synthesis of acute phase proteins (APPs). The acute phase response is signalled by the rapid elevation of APPs such as C-reactive protein (CRP) and serum amyloid A (SAA) in the blood, and these can be used as good surrogate markers of disease activity. In health, the activity of cytokines such as IL-1 or TNF is checked by inhibitory molecules such as receptor antagonist molecules or soluble receptor molecules. In disease, cytokine activity appears to be relatively unopposed, leading to the recent development of cytokine inhibitory molecules as potential anti-RA therapies. However, while cytokines are mediators of disease, they probably do not provide the initial stimulus for RA to develop, although polymorphisms in TNF, IL-1 and IL-1 receptor antagonist genes which have been recently found may represent important genetic modifying factors of disease severity in RA.