Review Article - Rheumatoid Arthritis & Il-6

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Review Article

RA: Interleukin-6, its roles and significance in the pathophysiology of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory autoimmune condition principally causing synovial joint inflammation and cartilage erosion. The pathogenesis encompasses intricate cellular and humoural manifestations, and vascular reactions that result in the infiltration of the synovium by white blood cells, of which release inflammatory mediators, inclusive of Interleukin-6 (IL-6). IL-6 serum levels of RA patients as shown by Capell et al. (1993) displayed a median of 55 IU/ml, as compared to that of healthy controls of 10 IU/ml. With a wide-ranging pleiotropy endorsed by both a membrane-bound (IL-6R) and soluble (sIL-6R) receptor, and by the relative omnipresence of the trans-membrane protein gp130, IL-6 endorses a pro-inflammatory effect via its influence on numerous cell types and signalling-pathways. As a result, heightened levels of IL-6 aids in the promotion of osteitis, sequential joint damage, pain/discomfort and impaired function in RA patients.

Pleiotropy of IL-6
Interleukin 6 exerts effects on numerous pathways contributing to the pathophysiology of RA. IL-6 as it is called today has been known by several names that exemplify its pleiotropy for example, hepatocyte-stimulating factor known to cause the induction of C-reactive protein (CRP); due to IL-6 association with synovial fibril aggregation has been known as Amyloid protein; a thrombopoietin; both B-cell differentiation and stimulating factor 2; plasmacytoma growth factor; and cytotoxic T-cell differentiation factor. It also causes the differentiation of Th17 cells; is a causative factor in adhesion molecule expression on the surface of endothelial cells, and is involved in the differentiation to mature from precursor osteoclasts cells (REF!!). IL-6

Recptor binding
IL-6 implements its influence via a protein complex primarily comprised of a membrane bound IL-6R and a glycoprotein comprised of two intra-cytoplasmic transducer sub-units, gp130. When IL-6 binds to membrane bound IL-6R (mIL-6R) it causes homo-dimerisation of the gp130 sub-units, of which triggers intra-cytoplasmic signal transduction. Whilst expression of gp130 is relatively omnipresent upon the surface of the body’s cells (Akil, et al., 2008), IL-6R is most prominently located on hepatocytes, macrophages, monocytes, neutrophils and select lymphocytes. However, (sIL-6R) of which is systemic also binds IL-6, and just as mIL-6R, can also engage with gp130 for sIL-6-gp130 trans-signalling (REF!). Synoviocytes, for example do not express mIL-6R but do express gp130. Raised levels of IL-6 in the synovium is a characteristic biomarker of RA (Attar, et al., 2010), and Kim, et al. (1996) states enhanced IL-6/sIL-6R in synovial fluid increased the risk of joint destruction, as IL-6 stimulates endothelial cells to express adhesion cytokines and other molecules of which attract inflammatory cells to synovial membrane (Romano, et al., 1997) thus could contribute to exemplifying the significance of sIL-6R in RA pathophysiology. sIL-6R is formed by either an incomplete proteolytic enzymic dissection of mIL-6R or alternative splicing of mRNA (REF!!). With the aforementioned ubiquitous nature of gp130, mIL-6R and systemic sIL-6R, increasing evidence REFERENCES SEE NOTES!! shows that a non-membrane bound, systemic, soluble gp130 (sgp130) found in higher circulatory concentrations than that of sIL-6, also binds IL-6/sIL-6R, thus functioning as a redundency factor inhibiting the cytoplasmic signal-transducing potential of mgp130 REFERENCES SEE NOTES!!, (IL-6/IL-6 receptor system and its role…) thus serving as a natural inhibitor of IL-6 signalling (IL-6/IL-6 receptor system and its role…).

Intracellular signalling
gp130 dimerisation brings Janus Kinases (JAKS), a receptor-associated protein complex, into close proximity causing a trans-activation of the two molecule types....
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