IL-3 Attenuates Collagen-Induced Arthritis by Modulating the Development of Foxp3+ Regulatory T Cells

Abstract

IL-3, a cytokine secreted by Th cells, functions as a link between the immune and the hematopoietic system. We previously demonstrated the potent inhibitory role of IL-3 on osteoclastogenesis, pathological bone resorption, and inflammatory arthritis. In this study, we investigated the novel role of IL-3 in development of regulatory T (Treg) cells. We found that IL-3 in a dose-dependent manner increases the percentage of Foxp3+ Treg cells indirectly through secretion of IL-2 by non-Treg cells. These IL-3–expanded Treg cells are competent in suppressing effector T cell proliferation. Interestingly, IL-3 treatment significantly reduces the severity of arthritis and restores the loss of Foxp3+ Treg cells in thymus, lymph nodes, and spleen in collagen-induced arthritis mice. Most significantly, we show that IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-α, and IL-1 and increases the production of anti-inflammatory cytokines IFN-γ and IL-10 in collagen-induced arthritis mice. Thus, to our knowledge, we provide the first evidence that IL-3 play an important role in modulation of Treg cell development in both in vitro and in vivo conditions, and we suggest its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases.

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

“…In addition, they induce expression of MMPs, which degrade cartilage matrix, thereby aggravating the degeneration of joints (15). We have previously shown that IL-3 is a potent inhibitor of osteoclast formation and pathological bone resorption in vitro (17)(18)(19)(20), and it protects cartilage and bone damage in murine models of inflammatory arthritis (20) and collagen-induced arthritis (21). In this study, we investigated the role of IL-3 in regulation of chondrocyte function in vitro and cartilage degradation in vivo in a mouse model of human OA.…”

“…The high affinity receptor for IL-3 consists of a heterodimer of IL-3-specific a-chain and a common b-chain, which is shared with GM-CSF and IL-5 (33). IL-3Ra is expressed by human hematopoietic stem cells (34), endothelial cells and monocytes (35), activated T cells (21), osteoclasts (17)(18)(19), osteoblasts, and MSCs (36). In this study, we report for the first time, to our knowledge, that both mouse and human chondrocytes express IL-3Ra at transcript and protein levels.…”

“…Because IL-3 has an anti-inflammatory activity in vitro and in vivo (20,21), we further investigated the effect of IL-3 on mouse chondrocytes in the presence of IL-1b. Mouse chondrocytes were incubated with IL-1b (5 ng/ml) and different concentrations of IL-3 for 24 h. IL-1b inhibited the expression of chondrocyte-specific genes including Sox9, Col2a, and aggrecan, and upregulated the expression of matrix-degrading enzymes, MMP-3 and MMP-13.…”

“…We have also shown that IL-3 is a potent inhibitor of pathological bone resorption induced by TNF-a and other proinflammatory cytokines such as IL-1a, TGF-b1, TGF-b3, IL-6, and PGE 2 (20). Recently, we demonstrated that IL-3 has anti-inflammatory activity in vivo and indirectly protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis (20,21). However, the role of IL-3 on chondrocyte differentiation and cartilage degeneration in OA is not yet known.…”

Response to Comment on “IL-3 Attenuates Collagen-Induced Arthritis by Modulating the Development of Foxp3+ Regulatory T Cells”

“…(6). Using a disease-specific animal model of human RA, we showed that IL-3 significantly increases the percentage of Foxp3 1 functional Treg cells in both in vitro and in vivo conditions (7).…”