The integrin α9β1 is a key receptor involved in the development of autoimmune diseases. However, the detailed mechanism for the association of α9β1 integrin with its ligands remains unclear. In this study, we introduce XCL1/lymphotactin, a member of the chemokine family, as a novel ligand for α9 integrin. Using α9 integrin-overexpressing NIH3T3 cells and endogenously α9 integrin-expressing human rhabdomyosarcoma cells, the interaction between XCL1 and α9 integrin was confirmed by pull-down assays. XCL1 enhanced α9 integrin-dependent cell migration of these cells, thus acting on α9 integrin as a chemoattractant. We also analyzed the in vivo function of XCL1 in the development of anti-type II collagen Ab-induced inflammatory arthritis (CAIA) in BALB/c mice and experimental autoimmune encephalomyelitis in C57BL/6 mice, because α9 integrin is involved in these autoimmune disease models. In CAIA, recombinant XCL1 aggravated the disease and this exacerbation was inhibited by an anti-α9 integrin Ab. An XCL1-neutralizing Ab produced in this study also ameliorated CAIA. Furthermore, the XCL1-neutralizing Ab abrogated the disease progression in experimental autoimmune encephalomyelitis. Therefore, to our knowledge this study provides the first in vitro and in vivo evidence that the interaction between XCL1 and α9 integrin has an important role for autoimmune diseases.
Cyclosporin A (CsA) is effective at reducing pathogenic immune responses, but upon withdrawal of CsA the immune response often “rebounds” resulting in a relapse or exacerbation of disease. The mechanisms, cells and cytokines involved in the relapse or exacerbation after CsA withdrawal are unknown. We hypothesized that CsA withdrawal induces IL-17 production that could be responsible for relapse, and examined the effect of anti-IL-17A antibody on relapse induced after CsA withdrawal in mouse experimental autoimmune encephalomyelitis (EAE). CsA treatment markedly decreased the EAE disease score during the first episode, but augmented disease severity after CsA withdrawal, compared to untreated mice. After discontinuation of CsA the production of IL-17A was increased and the severity of relapse in EAE was reduced by treatment with anti-IL-17A antibody. These results suggest that the resumption of T cell immune responses after CsA withdrawal leads to a burst of IL-17A production that is at least partially responsible for relapse in EAE mice.
Background: ␣4 Integrin participates in tumor metastasis and autoimmune diseases. Results: ␣4B Markedly inhibited ␣4 integrin-dependent cell adhesion through the cytoplasmic region of ␣4B. Conclusion: ␣4B Is a novel endogenous inhibitor of ␣4 integrin. Significance: This study provides a possible role of ␣4B as an inhibitor of ␣4 integrin-mediated metastasis.
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