TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice

Abstract

IL-1 receptor antagonist-deficient (IL-1Ra -/-) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra -/-mice did not develop arthritis, and transfer of IL-1Ra -/-T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-α deficiency. We found that TNF-α induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-α plays an important role in activating T cells through induction of OX40.

Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells

“…We also examined the function of T-bet in the IL-1 signaling pathway in the spontaneous arthritis that develops in the absence of the IL-1Ra on the BALB/c background (29,33). We crossed the T-bet-deficient strain onto the IL-1Ra-deficient strain and monitored arthritis in the DKO.…”

Animal models of arthritis caused by systemic alteration of the immune system

“…The IL-1Ra-deficient and the gp130 F759/F759 knock-in mice fail to develop arthritis in a RAG-deficient background [13,26 ]. Notably, the transfer of T cells or thymocytes from IL-1Ra-deficient mice can induce arthritis in syngeneic normal nude mice whether the donor mice are afflicted with the disease or not [26 ].…”

“…Notably, the transfer of T cells or thymocytes from IL-1Ra-deficient mice can induce arthritis in syngeneic normal nude mice whether the donor mice are afflicted with the disease or not [26 ]. In comparison to normal T cells, which secrete IL-1Ra, IL-1Ra-deficient T cells produce higher levels of cytokines such as TNF-a upon in vitro TCR stimulation.…”

“…In addition, deficiency of IL-17, a T-cell-specific pro-inflammatory cytokine, completely abrogates the development of arthritis in IL-1Ra-deficient mice [27]. IL-1Ra-deficient antigen-presenting cells (APCs) are more efficient than normal APCs in in vitro T cell activation [26 ]. These results taken together indicate that IL-1Ra deficiency might render T cells (and also APCs and synoviocytes) highly sensitive to IL-1, thereby leading to the activation of arthritogenic T cells by a physiological amount of IL-1 produced in the joint.…”

“…In arthritis induction by serum transfer from K/RxN mice, IL-1 deficiency substantially suppresses arthritis development, whereas TNF-a deficiency is partially suppressive and IL-6 deficiency has no diseasesuppressive effect [31]. TNF-a-deficiency markedly inhibits arthritis development in IL-1Ra-deficient mice whereas IL-6 deficiency exacerbates the disease [26 ]. IL-6 deficient hTNF-a-transgenic mice develop arthritis at a similar frequency as IL-6 intact transgenic mice whereas administration of anti-IL-R antibody prevents arthritis [32,33].…”