Interleukin-18 A Proinflammatory Stimulus In RA

[Guest guest]

Here's another one of those very technical but also very important

research articles. If anybody here has the ability to and cares to

explain this further, in layman's terms, please do

~Georgina

Interleukin-18 Acts As A Proinflammatory Stimulus In RA

http://www.hopkins%2Darthritis.com/news%2Darchive/2000/il18.html

Functionally distinct T-cell subsets, known as Th1 and Th2, are

recognized. In rheumatoid arthritis (RA), there is T-cell polarization

in which Th1 cells predominate and are thought to drive the inflammatory

response. It is unclear what initiates and sustains the Th1 response,

however, one potential explanation is over expression of interleukin-18

(IL-18). IL-18 exhibits synergy with IL-12 in promoting Th1 responses,

induces proliferation, upregulates IL-2Ra expression, and promotes TNF-a

, and GM-CSF production by Th1 clones. Gracie, et al (J Clin Invest

104:1393-1401, 1999) examined the role of IL-18 in promoting rheumatoid

synovitis.

Using RT-PCR significantly higher levels of IL-18 mRNA and protein were

detected in the synovial tissues of rheumatoid arthritis (RA) patients

as compared to those from osteoarthritis (OA) controls. To determine

distribution, synovia were stained with a mAB to human IL-18.

Lymphocytic aggregates stained most prominently for IL-18 expression,

primarily residing in CD 68+ macrophages. A small number of CD68-,

IL-18+ cells were

also detected, most likely fibroblasts. No staining for IL-18 was

detected in CD3+ lymphocytes. IL-18 receptor (IL-18R) mRNA was also

detected in 10 of 10 RA synovial membrane. Using FACS analysis, IL-18R

expression was detected in significant subpopulations of CD3+ synovial

fluid lymphocytes and CD14+ macrophages. Cytokine production was also

determined. IL-18, together with IL-12 or IL-15 induced significant

production of INF-g in synovial tissues in vitro and alone, promoted

GM-CSF and nitric oxide production. Using the murine collagen-induced

arthritis (CIA) model, mice developed high incidence and severity of

arthritis when IL-18 was coadministered with CII/IFA priming and

challenge when compared to controls that received CII/IFA alone.

These data confirm that IL-18 promotes articular Th1 responses but may

also act directly on macrophages to induce proinflammatory cytokine

production. That these effects may have pathophysiological significance

in RA is indicated by the ability of IL-18 to promote collagen-induced

arthritis in mice.