The Interleukin6 Family of Cytokines

Of the cytokines induced by IL-1 and TNF-a, IL-6 appears to play a dual role: it causes an increase in IL-1Ra, sTNFR, and tissue inhibitor of metalloproteins (TIMP), while also enhancing immune cell function and inflammation. Although early studies suggested a potential role for IL-6 as an intermediate, it was found later that the soluble IL-6 receptor (sIL-6R) is required for the full response to IL-6 in chondrocytes in vitro [80]. Interaction of IL-6 with sIL-6R permits syner-gistic stimulation of MMPs by IL-1 and IL-6 [186]. It also permits upregulation of MMP and ADAMTS and downregulation of COL2A1 and aggrecan in cultured chondrocytes via the JAK/STAT pathway [116,117]. On the other hand, physiologic levels of this cytokine may play a protective role, since IL-6 knockout mice develop OA more readily during aging [45].

Other members of the IL-6 family that act via receptors associated with the gp130 domain may also act as modulators. IL-11 has several effects similar to those due to IL-6, including stimulation of TIMP production without affecting MMP production by chon-drocytes [186]. Leukemia inhibitory factor (LIF), which is induced by IL-6, IL-1, or TNF-a, participates in a positive feedback loop by increasing the production of IL-6. Oncostatin M (OSM), another member of the IL-6 family that acts via the JAK/STAT pathway, is a potent stimulator of chondrocyte production of MMPs and aggrecanases in synergism with IL-1 or TNF-a [15,94]. Adenoviral overexpression of OSM alone or together with IL-1 induces synovial inflammation and hyperplasia and severe cartilage damage in mouse knee joints [185]. Since neutralizing OSM antibodies ameliorate cartilage damage in inflammatory arthritis, endogenously produced OSM may have a role distinct from that of IL-1 and TNF-a [171]. Paradoxically, OSM decreases

IL-1P-stimulated production of PGE2, NO, IL-8, and MIP-1^, but amplifies IL-1£ stimulated IL-6 production in OA chondrocytes that are cultured in alginate [191].

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