Background Experimental arthritis in Interleukin-6 deficient (IL-6-/-) mice has shown the importance of this cytokine for chronicity of the synovitis. We^1,2 and others have found previously that in IL-6 deficient mice the primary inflammation does not develop into a chronic synovitis. The JAK/STAT pathway is important for signaltransduction by IL-6 in the cell. Upon activation of the IL-6 receptor complex, the Signal Transducer and Activator of Transcription molecules STAT1 and STAT3 become phosphorylated and migrate to the nucleus to activate gene transcription.

Objectives In the present study we followed activation of STAT1 and 3 during zymosan-induced arthritis (ZIA) in wildtype (wt) and IL-6-/- mice. We also studied expression of the STAT inhibitors Suppressor Of Cytokine Signalling (SOCS) 1 and 3 during the arthritis.

Methods Zymosan induced Arthritis was elicited by intra-articular injection of zymosan as described in (2). Protein lysates of inflamed and control synovia were subjected to Western blotting for both total and phosphorylated STAT1 and STAT3. RT-PCR was performed for STAT3, SOCS1 and SOCS3.

Results The primary inflammation lasted for a week in both strains. In wt mice this inflammation became chronic until the end of the experiments at week 4, while it decreased rapidly in IL-6-/- mice. In wt mice STAT3 became activated from day 1 until the end of the experiments. Also the level of STAT3 mRNA and protein increased. STAT1 in contrast only became activated during the chronic phase after day7. During the arthritis there was an increase of SOCS1 and SOCS3 mRNA expression. In IL-6-/- mice STAT3 only became activated at day 1. No activation of STAT1 occurred in IL-6-/- mice.

Conclusion STAT3 activation occurred during both the primary and chronic inflammation in wildtype mice. During the first week IL-6-/- mice also developed a primary inflammation. IL-6 is not the only cytokine that activates STAT3, explaining STAT3 activation at day 1 in IL-6-/- mice. Lack of further STAT3 activation during the primary inflammation suggests a major role for IL-6 in STAT3 activation. STAT1 only became activated in the chronic phase. Arthritis increased expression of SOCS1 and 3, but this seemed not enough to inhibit STAT activation. Future research will have to address the importance of activated STAT1 and 3 for chronic synovitis and the possibility of inhibiting these signalling molecules in the inflamed synovium.

References

1. de Hooge ASK, van de Loo FAJ, Arntz OJ, van den Berg WB. Involvement of IL-6, apart from its role in immunity, in mediating a chronic response during experimental arthritis. Am J Pathol. 2000;157:2081–91

2. van de Loo FAJ, Kuiper S, van Enckevort FH, Arntz OJ, van den Berg WB. Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6 deficient mice. Am J Pathol. 1997;151:177–91