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A10.02 Deficiency in IL-1 receptor type 2 aggravates K/BXN serum transfer-induced arthritis in mice, but has no effect in endotoxemia
  1. P Martin1,2,
  2. G Palmer1,2,
  3. E Rodriguez1,2,
  4. CA Seemayer3,
  5. D Talabot-Ayer1,2,
  6. C Gabay1,2
  1. 1Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland
  2. 2Division of Rheumatology, University Hospital, Geneva, Switzerland
  3. 3Global Clinical Science and Epidemiology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

Abstract

Introduction The biological activity of interleukin (IL)-1 is tightly regulated by a specific receptor antagonist (IL-1Ra) and the decoy receptor 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.

Methods We generated IL-1R2 deficient mice in a C57BL/6 background and investigated the role of IL-1R2 in both lipopolysaccharide (LPS)-induced lethality by injecting 10 mg/kg E. coli LPS intraperitoneally (i.p.), and in systemic inflammatory responses induced by i.p. injections of 10 µg/kg IL-1β. Lethality was monitored daily and serum cytokine levels were measured at different time points by ELISA, respectively. Arthritis was induced by injecting i.p. 1.5 mg purified arthritogenic IgGs purified from K/BxN serum. Arthritis severity was assessed by clinical and histological scoring. Tissue mRNA levels of cytokines were measured by real-time PCR.

Results IL-1R2 deficient mice bred normally and exhibited a grossly normal phenotype. IL-1R2 was selectively expressed by wild-type (WT), but not IL-1R2 deficient, neutrophils. The number of immune cells in bone marrow, spleen and peripheral blood was similar in IL-1R2 deficient and WT mice. The phagocytic function and oxidative burst of IL-1R2 deficient neutrophils were normal. The rate of LPS-induced mortality and the level of inflammatory responses to IL-1b were similar in IL-1R2 deficient mice and their WT littermates. In contrast, IL-1R2 deficiency was associated with aggravated arthritis severity. Levels of IL-6, IL-1β, CXCL-1 and CXCL-2 mRNA were significantly increased in ankles of IL-1R2 deficient mice. Immunohistochemical analyses indicated that IL-1R2 is mainly expressed by infiltrating neutrophils.

Conclusions These data show that the decoy receptor IL-1R2 plays an important role during K/BxN serum transfer-induced inflammatory arthritis and suggest that neutrophils exert anti-inflammatory activities in arthritis by expressing IL-1R2. However, in contrast to IL-1Ra, IL-1R2 is not essential for normal homeostasis and systemic responses to LPS and acute IL-1 administration.

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