**7.1. IL-18**

IL-18 is structurally similar to IL-1 and the IL-18 receptor is a member of the IL-1R/TLR pro‐ tein superfamily [128]. However, the function of IL-18 differs considerably from that of IL-1 and, in fact unlike IL-1, IL-18 is produced by a variety of immune as well as non-immune cells. Although IL-18 in its role as a stimulator of Th1 responses is well known by its activity as an immune defense cytokine against microbial infection, the over-production of IL-18 can result in autoimmune disease via its capacity to modify and accentuate adaptive immuno‐ logical responses such as those seen in RA [129-132]. However, paradoxically IL-18 can also stimulate Th2-related cytokine responses as well [128]. Thus, its putative role in altering the Th1/Th2 cytokine repertoire cannot be dismissed.

Particularly important with regard to the role played by IL-18 in RA were results of a study by Gracie et al. [133] who first identified abundant IL-18 in RA synovial tissue. These find‐ ings are relevant when coupled with those from other studies by Tanaka et al. [134] who al‐ so found elevated IL-18 and the IL-18 receptor α/β in RA synovial tissue. They also demonstrated that IL-18 was a co-factor and regulatory cytokine in stimulating the synthesis of IFN-γ by T-cells in RA synovial tissue, the latter also requiring IL-12, thus implicating the up-regulation of IL-18 gene expression as an important component of RA disease progres‐ sion.

Activated STAT3 was identified as the JAK/STAT-related transcription factor responsible for the increased synthesis of IL-18 [127]. In that regard, TNF-α was shown to increase IL-18 gene expression in RA synoviocyte cultures suggesting the possibility that TNF-α, a known activator of p38 kinase and JNK may also activate STAT3 in synoviocyte and chondrocyte cultures. Indeed, recent results from our laboratory showed that recombinant human TNF-α activated STAT3 in normal human chondrocyte cultures and TNF-α activated STAT3, p38 kinase and JNK in cultured chondrocytes derived from human osteoarthritic knee cartilage [Malemud et al. submitted]. Thus, it was instructive to learn that treating RA patients with the combination therapy of infliximab and methotrexate reduced the level of IL-18 in serum whilst the level of the chemokine, CXCL12 was unaltered [135]. Moreover, synovial fluid from these RA patients had higher levels of IL-18 (as well as TNF-α and IL-15) prior to be‐ ginning combination therapy with infliximab and methotrexate compared to the level of these cytokines in a patient's sera. In addition, the level of IL-18/TNF-α in synovial fluid was strongly correlated with a patient's high Disease Activity Score-28 [136]. Thus, it may be in‐ formative going forward to assess the level of activated STAT3 and IL-18 in the synovial flu‐ id and sera of RA patients before and after treatment with TNF antagonists or other biological drugs that neutralize the activation of JAK/STAT and MAPK pathways to deter‐ mine the extent to which the level of activated STAT3, p38 kinase or JNK is correlated with IL-18 gene expression by synovium and cartilage *ex vivo*.
