Deficiency in IL-1 Receptor Type 2 Aggravates K/BxN Serum Transfer-Induced Arthritis in Mice but Has No Impact on Systemic Inflammatory Responses

The biological activity of IL-1 is tightly regulated by the specific receptor antagonist ( IL-1Ra) and the decoy receptor IL-1 receptor type 2 ( IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra-deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown. To define the functional role of endogenous IL-1R2 in the K/ BxN serum transfer arthritis model and in IL-1 beta-or LPS-induced systemic inflammation in vivo, IL-1R2(-/)-mice were created and compared with wild type mice. IL-1R2(-/)-mice bred habitually and exhibited a normal phenotype. IL-1R2 deficiency aggravated arthritis severity and increased mRNA levels for key cytokines and chemokines such as IL-6, IL-1 beta, Cxcl-1, and Cxcl-2 significantly in ankles. There was no effect of IL-1R2 deficiency on the cell-autonomous cytokine response to IL-1 beta in the tested cell types, i. e., neutrophils, macrophages, and fibroblasts, but IL-1R2 deficiency on neutrophils increased the IL-1-induced response of fibroblasts in trans. Furthermore, IL-1b induced shedding of IL-1R2 in vivo. Inflammatory responses to IL-1b and LPS-induced mortality were not different in IL-1R2 2/ 2 compared with wild type mice. Our data demonstrate that the decoy receptor IL-1R2 plays an important inhibitory role in local IL-1-and neutrophil-dependent tissue inflammation as shown in the K/ BxN serum transfer arthritis model. In contrast to IL-1Ra, IL-1R2 appears to be less crucial for systemic responses to acute administration of IL-1 or LPS.