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].

Was this article helpful?

0 0
Arthritis Relief Now

Arthritis Relief Now

When you hear the word arthritis, images of painful hands and joints comes into play. Few people fully understand arthritis and this guide is dedicated to anyone suffering with this chronic condition and wants relief now.

Get My Free Ebook

Post a comment