Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Abstract

Introduction (also known as IL-17E) is a recently described member of the IL-17 cytokine gene family. IL-25 is made by several cell types, including T lymphocytes, mast cells, eosinophils, and basophils. 1,2 IL-25 can also be produced by lung epithelial cells and alveolar macrophages on allergen stimulation. 3,4 Unlike other members of the IL-17 family, IL-25 facilitates pathogenic Th2 cell responses. Studies in mice have shown that transgenic expression of IL-25, or systemic administration of recombinant cytokine, increases the production of IL-4, IL-5, and IL-13. The induction of these cytokines is also associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. [4][5][6][7] However, studies in murine models of autoimmunity have shown that IL-25 can negatively regulate the development, amplification, or both of Th17-mediated disorders, 8 thus suggesting that IL-25 may both trigger and abrogate specific inflammatory responses. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 can differentially regulate immune reactions are not well known.IL-25 biologic activity is mediated by a transmembrane receptor (IL-25R), also called IL-17BR or IL-17R homolog 1, that is constitutively expressed in the liver, kidney, and intestine. 9 Although T cells, and particularly Th2 memory cells, express high levels of IL-25R, 10 a non-B-/non-T-cell population is also a major target of IL-25, because this cytokine can boost robust cytokine responses in recombinase-activating gene (RAG) knockout mice. 5 Moreover, studies with RAG knockout splenocytes showed that the IL-25-responding cell is an accessory cell that expresses high levels of MHC class II and low levels of CD11c, 5 raising the possibility that IL-25 may control the activity of antigen-presenting cells. In this study, we aimed at further characterizing the cellular targets of IL-25R. We show that IL-25R is highly expressed by human blood CD14 ϩ cells, and that these cells respond to IL-25 by down-regulating the expression of inflammatory cytokines induced by toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS) and peptidoglycan (PGN) or inflammatory cytokines (ie, tumor necrosis factor ␣ [TNF-␣] and interferon ␥ [(IFN)-␥]). Inhibition of cytokine responses by IL-25 occurs via a p38 mitogen-activated protein (Map) kinase-driven suppressor of cytokine signaling 3 (Socs-3) induction-dependent mechanism. We also show that IL-25 inhibits inflammatory cytokines in vivo and protects against LPS-induced lethal endotoxemia. Overall, these data indicate that IL-25 is a negative regulator of CD14 ϩ cell cytokine response and that IL-25 therapy may be useful for attenuating monocyte-mediated disorders. Methods Cell isolation and cultureAll reagents were from Sigma-Aldrich (Milan, Italy) unless specified. Human peripheral blood mononuclear cells (PBMCs) were isolated from enriched buffy coats of healthy volunteer donors by Ficoll gradients and used to assess IL-25R. PBMCs were...

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury

“…1,5 However, IL-25 also plays a critical role in suppressing intestinal chronic inflammation, regulating adipose tissue inflammation and protecting against LPS-induced lethal endotoxemia. 3,25,26 We have demonstrated that IL-25 attenuated renal injury in AN, a model of CKD, whereas the potential role of IL-25 in acute kidney disease is unclear. AKI induced by IRI is associated with an acute reduction of blood flow that produces hypoxiainduced vascular and tubular dysfunction.…”

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

“…There are several reports that have implicated p38 MAPK in playing a major role in induction of SOCS3 (32,(65)(66)(67). Because earlier we found that PPE18 interacts with the LRR 11-15 domain of TLR2 and leads to an early and sustained activation of p38 MAPK, which was critical for IL-10 induction (24), it was reasonable to expect that PPE18 increased the SOCS3 levels in THP-1 macrophages via activation of p38 MAPK.…”

“…Several reports have implicated a prominent role of p38 MAPK signaling in SOCS3 induction (32,(65)(66)(67). In our previous study, we found that PPE18 induces early activation of p38 MAPK, which is in turn necessary for the IL-10 induction via TLR2 (24).…”

T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma

“…IL-25R also is expressed on human eosinophils, monocytes, airways smooth muscle cells, and fibroblasts (16)(17)(18)(19), raising the possibility that IL-25 also may be involved in causing structural changes in the airways that characterize asthma. However, its possible role in angiogenesis has never been explored.…”