Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis

Arthritis Res Ther. 2010;12(4):R140. doi: 10.1186/ar3079. Epub 2010 Jul 13.

Abstract

Introduction: Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA.

Methods: Rats with AIA were either treated with sgp130 or saline intra-peritoneally or intra-articularly (each group n = 9). Then, pain-related and locomotor behaviour, as well as joint swelling, were measured during an observation period of 21 days, followed by histopathological end-point analysis for inflammatory and destructive changes.

Results: A single intra-articular application of sgp130 at the time of AIA induction barely reduced the development of AIA, but significantly attenuated pain-related behaviour, that is, primary mechanical hyperalgesia in the acute phase of AIA. By contrast, repeated systemic application of sgp130 after onset of AIA only slightly attenuated pain at a late stage of AIA. None of the treatments reduced secondary hyperalgesia. Furthermore, in the present study joint destruction at 21 days was significantly attenuated after intra-articular sgp130 treatment, but not after systemic sgp130.

Conclusions: In addition to its role in chronic inflammation, IL-6 in the joint plays a significant role in the generation and maintenance of arthritic joint pain at acute and chronic stages of AIA. The particular effectiveness of intra-articular injection of sgp130 indicates, first, that IL-6/sIL-6R in the inflamed joint, rather than circulating IL-6/sIL-6R, is responsible for the generation of hyperalgesia, and, second, that early neutralization of IL-6/sIL-6R is particularly successful in producing antinociception. Furthermore, neutralization of IL-6/sIL-6R (and possibly other cytokines which use the transmembrane signal-transducing subunit gp130) directly at the site of joint inflammation seems to be effective in the prevention of joint destruction.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Behavior, Animal / drug effects
  • Female
  • Glycoproteins / metabolism
  • Glycoproteins / pharmacology*
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Injections, Intra-Articular
  • Injections, Intraperitoneal
  • Interleukin-6 / metabolism
  • Motor Activity / drug effects
  • Pain / drug therapy*
  • Pain / metabolism
  • Pain / pathology
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • Solubility

Substances

  • Glycoproteins
  • Interleukin-6
  • glycoprotein 130, human