1. The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Underscore the Therapeutic Rationale for Dual Blockade.
- Author
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Hillen MR, Hartgring SA, Willis CR, Radstake TR, Hack CE, Lafeber FP, and van Roon JA
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Arthritis, Experimental genetics, Arthritis, Experimental immunology, Arthritis, Rheumatoid immunology, Cytokines genetics, Humans, Inflammation genetics, Inflammation immunology, Mice, Mice, Knockout, Thymic Stromal Lymphopoietin, Arthritis, Experimental metabolism, Arthritis, Rheumatoid metabolism, Cytokines metabolism, Inflammation metabolism, Interleukin-7 metabolism, Receptors, Interleukin-7 immunology, Signal Transduction drug effects
- Abstract
Introduction: The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied., Methods: Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed., Results: Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors., Conclusion: TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA.
- Published
- 2015
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