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-1β– 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-1β, Cxcl-1, and Cxcl-2 significantly in ankles. There was no effect of IL-1R2 deficiency on the cell-autonomous cytokine response to IL-1β 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-1β induced shedding of IL-1R2 in vivo. Inflammatory responses to IL-1β and LPS-induced mortality were not different in IL-1R2−/− 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.
This work was supported by grants from the Swiss National Science Foundation (310030_152638 to C.G.), the Institute of Arthritis Research, the Rheumasearch Foundation, the Uniscentia Foundation, and the de Reuter Foundation.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- bone marrow–derived macrophage
- collagen-induced arthritis
- embryonic stem
- geometric mean fluorescence intensity
- human serum albumin
- immune complex
- IL-1 receptor type 1
- IL-1 receptor type 2
- IL-1 receptor antagonist
- quantitative real-time PCR
- rec. m
- recombinant mouse
- wild type.
- Received May 18, 2016.
- Accepted January 30, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.