Abstract
Recent studies have identified CD74, the cell surface form of the class II-associated invariant chain, as a binding site for the cytokine macrophage migration inhibitory factor (MIF). MIF is implicated in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, but a functional relationship between MIF and CD74 in inflammation has not been demonstrated. We used CD74-/- mice to examine the role of this molecule in cellular and in vivo inflammatory responses, using innate immune response-dependent models to avoid confounding by the role of MHC Ii in adaptive immunity. MIF has a demonstrated role in macrophage responses to endotoxin. LPS induced IL-1, IL-6, TNF and MIF release from WT bone-marrow macrophages. Bone-marrow macrophages lacking CD74 released significantly lower amounts of IL-1 and IL-6, but no difference in TNF release was evident. LPS-induced MIF release by WT and CD74-/- bone-marrow macrophages was also similar. Murine K/BxN serum-transfer arthritis is MIF dependent [1], and also requires the induction of IL-1. Compared with WT mice, arthritis severity (clinical score) was significantly lower in mice lacking CD74 (P < 0.05). These data imply but do not demonstrate a role of CD74 in MIF-dependent inflammatory responses. To confirm the role of CD74 in responses to MIF in vivo, we examined a recently described action of MIF – the induction of leukocyte trafficking [2]. rhMIF was injected into mouse cremaster tissue and leukocyte–endothelial interactions examined using intravital microscopy. MIF induced leukocyte adhesion and emigration in vivo in WT mice. In CD74-/- mice, in contrast, this response could not be elucidated. These data demonstrate for the first time the role of CD74 in innate immune responses and inflammatory arthritis, and demonstrate for the first time in vivo the requirement for CD74 for the action of MIF. A functional role for CD74 in MIF responses in inflammation is strongly supported.
Highlights
Rheumatoid arthritis is a chronic inflammatory disorder that primarily affects the joints and results in the destruction of cartilage and subchondral bone by the inflamed synovium
peripheral blood mononuclear cells (PBMC) from systemic sclerosis (SSc) patients responded to TNFα with significantly higher production of leukotriene E4 (LTE4) in comparison with healthy controls (P < 0.05 at 1 hour), while there were no significant differences in TNFα-induced production of 15-hydroxyeicosatetraenoic acid (15-HETE) between SSc patients and controls
It was shown that attachment of synovial fibroblasts (SF) that this association was completely dependent on concomitant from rheumatoid arthritis patients to laminin-111 (LM-111) induced carriage of the PSORS1 risk allele
Summary
Rheumatoid arthritis is a chronic inflammatory disorder that primarily affects the joints and results in the destruction of cartilage and subchondral bone by the inflamed synovium. A observed in affected joints of rheumatoid arthritis (RA) patients, as tourniquet was not used during the procedures and the skin portal well as extensive synovial infiltration of inflammatory cells. These conflicting observations suggest that the regulation of IL-7 expression is tightly controlled at the level of tissue specificity To support this hypothesis, we showed that several cytokines have a different effect on IL-7 production in BM StrC, epithelial cells from the liver and gut. TRU-015 is a CD20-directed small modular immunopharmaceutical drug candidate that effectively depletes B lymphocytes in cynomolgus monkeys in a dose-dependent manner, and improves survival in mouse xenograft tumor models [4,5].
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