Interleukin 10 (IL-10) and IL-4 are important downregulators of a number of macrophage functions. The authors investigated the role of endogenous IL-4 and IL-10 and the therapeutic effect of addition of these cytokines on joint inflammation and cartilage destruction in the early stages of the macrophage dependent murine streptococcal cell wall (SCW) arthritis model. It was demonstrated that endogenous IL-10, but not IL-4, plays a pivotal role in the regulation of SCW arthritis. Blocking endogenous IL-10 with anti-−IL-10 antibodies resulted in a sustained arthritis with more dense synovial infiltrate as well as enhanced cartilage damage. Adding exogenous −IL-10 further enlarged the suppressive effect of endogenous IL-10. Even more pronounced amelioration was found with the combination −IL-4/−IL-10. This resulted in a reduced swelling and a restorative overshoot in chondrocyte proteoglycan synthesis at day 4 (140%). Treatment with the combination −IL-4/−IL-10 not only gave a marked reduction of tumour necrosis factor α (TNF-α) levels, like IL-10 treatemnt alone, but also the IL-1β levels were strongly reduced in the synovium. In conclusion, the data is onsistent with a dominant role of IL-10 in natural suppression of arthritis expression, whreas combined treatment with IL-4 and IL-10 appears to be of potential therapeutic value.