Enhancing Effect of IL-1, IL-17, and TNF-α on Macrophage Inflammatory Protein-3α Production in Rheumatoid Arthritis: Regulation by Soluble Receptors and Th2 Cytokines

Abstract

Macrophage inflammatory protein (MIP)-3α is a chemokine involved in the migration of T cells and immature dendritic cells. To study the contribution of proinflammatory cytokines and chemokines to the recruitment of these cells in rheumatoid arthritis (RA) synovium, we looked at the effects of the monocyte-derived cytokines ΙL-1β and TNF-α and the T cell-derived cytokine IL-17 on MIP-3α production by RA synoviocytes. Addition of ΙL-1β, IL-17, and TNF-α induced MIP-3α production in a dose-dependent manner. At optimal concentrations, ΙL-1β (100 pg/ml) was much more potent than IL-17 (100 ng/ml) and TNF-α (100 ng/ml). When combined at lower concentrations, a synergistic effect was observed. Conversely, the anti-inflammatory cytokines IL-4 and IL-13 inhibited MIP-3α production by activated synoviocytes, but IL-10 had no effect. Synovium explants produced higher levels of MIP-3α in RA than osteoarthritis synovium. MIP-3α-producing cells were located in the lining layer and perivascular infiltrates in close association with CD1a immature dendritic cells. Addition of exogenous IL-17 or ΙL-1β to synovium explants increased MIP-3α production. Conversely, specific soluble receptors for ΙL-1β, IL-17, and TNF-α inhibited MIP-3α production to various degrees, but 95% inhibition was obtained only when the three receptors were combined. Similar optimal inhibition was also obtained with IL-4, but IL-13 and IL-10 were less active. These findings indicate that interactions between monocyte and Th1 cell-derived cytokines contribute to the recruitment of T cells and dendritic cells by enhancing the production of MIP-3α by synoviocytes. The inhibitory effect observed with cytokine-specific inhibitors and Th2 cytokines may have therapeutic applications.

Stimulus-specific Induction of a Novel Nuclear Factor-κB Regulator, IκB-ζ, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization

“…Total RNA was extracted and subjected to Northern blot analyses with a probe for IB-, IB-␣, or G3PDH. though IL-17 has been reported to activate NF-B and MAP kinases (35,51), these activities were not detected under our current experimental conditions. It has been suggested that IL-17 signaling requires TRAF6 but not TRAF2 (52,53).…”

Potential Interaction between CCR1 and Its Ligand, CCL3, Induced by Endogenously Produced Interleukin-1 in Human Hepatomas

“…[45][46][47][48][49][50] IL-1 and TNF induced CCL3 and CCL4 production by several hepatoma cell lines and an immunohistochemical analysis demonstrated the presence of IL-1␣ and IL-1␤ in hepatoma tissues. Thus, it is reasonable to speculate that endogenously produced IL-1 induces CCL3 production in an autocrine and/or paracrine manner.…”

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…These interventions can reduce IL-17-driven production of inflammatory factors such as leukaemia inhibitory factor [61], CCL20/MIP3a [70] as well as decreasing matrix metalloproteinase (MMP) production and increasing tissue inhibitors of MMPs [67]. Some of the effects of IL-17 on articular cartilage can be attenuated by this approach in vivo [64], while blockade of IL-17 abrogates completely the spontaneous development of inflammatory arthritis in IL-1R antagonist-deficient mice [71], and mice lacking IL-17 are highly resistant to CIA [72].…”