Mechanism of action of IL-1

IL-1 as a Therapeutic Target–Role of IL-1Ra
The role of interleukin-1 (IL-1) has been elucidated by studies that have examined the effects of endogenous IL-1 receptor antagonist (IL-1Ra). In the normal joint, endogenous IL-1Ra competes with IL-1 for binding to IL-1 receptor type I (IL-1RI) on target cells.^1,2 Unlike IL-1, binding of IL-1Ra to IL-1RI prevents the docking of the IL-1 receptor accessory protein (IL-1R AcP) to form the heterotrimeric complex that is necessary for signal transduction and therefore inhibits IL-1-mediated effects.^1,3,4 Thus, IL-1Ra is an important physiological regulator of synovial IL-1 activity.^1,4-9 However, analysis of synovial explants suggests that the rheumatoid synovium is characterised by an imbalance between IL-1Ra and IL-1 production, in favour of elevated IL-1.^10,11 These elevated levels of IL-1 cannot be counteracted sufficiently by endogenous IL-1Ra (Figure 1).^8,10,11 IL-1, therefore, binds to IL-1 receptors at a higher rate and perpetuates the proinflammatory response.^1,2,4,11-14

IL-1Ra is the most important physiological regulator of synovial activity

Figure 1. IL-1 inhibition with IL-1Ra^10,11
	IL-1Ra is the endogenous receptor antagonist inhibiting IL-1-mediated effects.¹⁰
	IL-1Ra competitively inhibits the binding of IL-1 to the IL-1 receptor.¹⁰
	IL-1Ra is the most important physiological regulator of synovial IL-1 activity.¹⁰
	RA patients show an imbalance between IL-1 and IL-1Ra levels.^10,11
	In RA, IL-1 levels can not be sufficiently countered by endogenous IL-1Ra^10,11

The results of animal experiments have also supported the existence of an imbalance between IL-1 and IL-1Ra in RA.^1,4,8,10,15 In a study of IL-1Ra-deficient (knockout) mice that spontaneously develop rheumatoid arthritis (RA), proinflammatorycytokines, including IL-1, were found to be overexpressed resulting in joint-specific inflammation; this emphasises the importance of the balance between IL-1 and IL-1Ra in maintaining normal physiology of the joints.⁸ Van den Berg and colleagues¹⁶ demonstrated that inflammation was ameliorated and that previously suppressed chondrocyte activity was normalised in mice with collagen-induced arthritis (CIA) treated with IL-1Ra. Such findings have been confirmed by van Lent et al¹⁷ who observed that neutralisation of IL-1 blocked the inhibition of proteoglycan synthesis. In this study, blocking of tumour necrosis factor-alpha (TNF-α) did not appear to have an effect on swelling, cell influx, proteoglycan synthesis, or proteoglycan degradation.¹⁷

RA patients exhibit an imbalance of IL-1 and IL-1Ra levels

Selective Inhibition of IL-1
Overexpression of IL-1 and the imbalance of IL-1 and IL-1Ra, have been implicated in the destructive tide of events in RA.^4,7,10,11,12 Kineret® (anakinra) counteracts the damaging cellular events in RA and reduces pain and inflammation (Figure 2).^3,5,9,10,18
Kineret® (anakinra) is a recombinant, non-glycosylated form of human IL-1Ra that exerts its action in the same manner as the endogenous antagonist.^1,19,20 Kineret® (anakinra) neutralises the biological activity of IL-1 by competitively inhibiting IL-1 binding to IL-1RI.^1,19,20 Binding of IL-1 to IL-1RI is necessary for the recruitment of the IL-1R AcP, and formation of the heterotrimeric complex, IL-1/IL-1RI/IL-1R AcP, which results in signal transduction. In vitro studies have shown that Kineret® (anakinra) inhibits responses such as the induction of nitric oxide and prostaglandin-E₂, and collagenase production by synovial cells, fibroblasts and chondrocytes.^1,19-21

Kineret® (anakinra) competitively inhibits the binding of IL-1 to IL-1RI, and blocks the deleterious effects of IL-1

Figure 2. Kineret® (anakinra) selectively blocks the effects of IL-1 in patients with RA^3,5,7,10
	The active ingredient of Kineret® (anakinra) is the first recombinant form of the naturally occurring human IL-1Ra.¹⁹
	Treatment with Kineret® (anakinra) helps to counteract the damaging cellular events mediated by IL-1 in RA, reducing pain and inflammation.^3,5,7,10

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References

(Click below to visualise the complete reference)

1.	Bresnihan B, et al. 1998
2.	Arend WP, et al. 1995
3.	Gabay C, et al. 2000
4.	Arend WP, et al. 1993
5.	Dinarello CA, et al. 2000
6.	Cohen S, et al. 2002
7.	Bresnihan B, et al. 1998
8.	Horai R, et al. 2000
9.	Schiff MH, et al. 2000
10.	Arend WP, et al. 2000
11.	Chomarat P, et al. 1995
12.	Firestein GS, et al. 1998
13.	Dayer JM, et al. 1977
14.	Dinarello CA, et al. 1987
15.	van den Berg WB, et al. 1999
16.	van den Berg WB, et al. 1999
17.	Van Lent PL, et al. 1995
18.	Cunnane G, et al. 2001
19.	Kineret® (anakinra) [summary of product characteristics]. Europe B.V. 2003
20.	Kineret® (anakinra) FDA Briefing Information, August 16, 2001
21.	Jiang Y, et al. 2000

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