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Interleukin 18: a pleiotropic participant in chronic inflammation

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Abstract

The wide-ranging effects of interleukin 18 as a regulator of innate and acquired immune responses, and particularly its role in human autoimmune diseases, suggest its potential importance as a therapeutic target.

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Biology of IL-18

Pro-IL-18 expression is widespread, and has been detected in many cell types including monocytes/macrophages, dendritic cells (DCs), Kupffer cells, keratinocytes, articular chondrocytes, synovial fibroblasts and osteoblasts, as well as within the adrenal cortex and pituitary gland2. Pro-IL-18 is cleaved by IL-1β-converting enzyme (ICE; caspase 1) to yield an active 18 kDa glycoprotein3. Alternate processing by caspase 3 or 4, or proteinase 3, is also postulated4. IL-18 recognizes a

IL-18 expression and function in inflammatory disease

The biological profile described above renders IL-18 a candidate pro-inflammatory cytokine in several autoimmune diseases. Indeed, IL-18 has recently been detected in the synovial compartment of patients with rheumatoid arthritis (RA)13. Whereas IL-18 mRNA was found in both RA and osteoarthritis (OA) synovial membranes (SMs), IL-18 protein was reproducibly detected by histology and ELISA only in RA-derived tissues. IL-18 expression was localized in RA SMs in cells of dendritic morphology within

Significance of IL-18 expression?

Although generally of a pro-inflammatory nature, not all activities thus far ascribed to IL-18 may be detrimental (Box 1). IL-18 directly suppresses angiogenesis, a process of demonstrable importance in inflammatory synovitis18. Moreover, IL-18 may inhibit osteoclast maturation through GM-CSF production, thereby retarding bone erosion. Suppression of COX expression may also be mediated through IFN-γ production.

We have therefore investigated the relative importance of IL-18 in articular

Concluding remarks

Data generated thus far indicate that IL-18 synergistically contributes both to host defence and to inflammation in a cascade of cytokines associated with innate responses, including IL-12 and IL-15 (Fig. 1). In this respect, IL-18 could modulate inflammation at multiple check points, acting not only on initiation and expansion of putative autoreactive Th/c1 responses, but also during perpetuation of synovial inflammation, independent of IFN-γ production, with direct effects on multiple

Acknowledgements

We thank the Arthritis Research Campaign (UK), The Wellcome Trust, The Scottish Chief Scientist Office and the Medical Research Council (UK) for their invaluable support.

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