The Adaptor Protein CIKS/Act1 Is Essential for IL-25-Mediated Allergic Airway Inflammation

Abstract

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c ؉ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

“…heterotypic SEFIR domain association (22,23). Consistent with a pathogenic role for IL-17 cytokines in various diseases, CIKS is critical for the development of collagen-induced arthritis, lupus, and asthma in mouse models (24)(25)(26).…”

IL-17-induced NF-κB Activation via CIKS/Act1

“…Furthermore, IL-25, another member of the IL-17 family that signals via CIKS, has been implicated in asthma, as it induces a strong Th-2-like innate response that also promotes Th2 adaptive responses thought to underlie most cases of asthma (16,17,47). Thus it might be useful to develop a means to block IL-17 cytokine signaling in such diseases.…”

“…Cell Culture and Reagents-Primary mouse embryo fibroblast cultures (MEFs) were established from wild-type (WT) and CIKS-deficient (knockout) mice as described previously (16). Mice were bred and housed in National Institute of Allergy and Infectious Diseases facilities, and all experiments were done with approval of the National Institute of Allergy and Infectious Diseases Animal Care and Use Committee and in accordance with all relevant institutional guidelines.…”

“…2C). To further delimit the critical sequences, we generated four point mutations in the domain between positions 10 and 21, replacing Ser 13 , Val 16 , Glu 17 , or Asp 19 with Ala (S13A, V16A, E17A and D19A); in addition we generated a combined mutant in which all four positions were replaced ("Quad"). As shown in Fig.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…9 Similar to IL-17RA, IL-17RB harbours a conserved SEFIR domain in the intracellular region and can recruit Act1 via the SEFIR-SEFIR interaction upon IL-17E stimulation. 54 The conditional deletion of Act1 in epithelial cells and T cells blocks allergen-induced airway inflammation. 55,56 Epithelialderived Act1 is also required for IL-17E-mediated parasite expulsion through the expansion of intestinal Lin -c-Kit + immune cells.…”