IL-17 family cytokines such as IL-17 (aka IL-17A), the closely related IL-17F, IL-17C and IL-25 have been implicated in the pathogenesis of various inflammatory and autoimmune diseases. In order to devise strategies to disable signaling by these cytokines in diseases, it is imperative to understand the pathways and molecular mechanisms by which these cytokines transmit signals in target cells to effect gene expression. In the past we have cloned an adaptor protein (CIKS) and demonstrated that this protein is absolutely required for signaling by IL-17 family cytokines and their pathogenic effects in disease contexts. Previously we also identified a critical N-terminal domain within the CIKS adaptor protein that mediates a functionally relevant interaction with Traf6, which is required in turn for activation of the NF-kappaB transcription factor, an important downstream effector of IL-17-induced expression. In FY 2013 we have begun to investigate potential roles of other transcription factors in IL-17 cytokines signaling that are known to help control inflammatory responses. In FY 2013 we have also begun to assess whether CIKS-mediated signaling can play a role apart from its obligate role in signaling by IL-17 cytokines. Initial collaborative studies have suggested a possible role of CIKS in responses to reactive oxygen species in some cell types. We are now developing a biologic approach to investigate this in greater depth. In FY2013 we have begun to devise assays to allow for high-throughput screening of agents that may interfere with signaling by IL-17 cytokines.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$174,392
Indirect Cost
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State
Country
Zip Code
Valente, Anthony J; Sakamuri, Siva S V P; Siddesha, Jalahalli M et al. (2013) TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cell Signal 25:2176-84
Venkatesan, Balachandar; Valente, Anthony J; Das, Nitin A et al. (2013) CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. Cell Signal 25:359-71
Valente, Anthony J; Yoshida, Tadashi; Clark, Robert A et al. (2013) Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free Radic Biol Med 60:125-35
Valente, Anthony J; Yoshida, Tadashi; Izadpanah, Reza et al. (2013) Interleukin-18 enhances IL-18R/Nox1 binding, and mediates TRAF3IP2-dependent smooth muscle cell migration. Inhibition by simvastatin. Cell Signal 25:1447-56
Valente, Anthony J; Clark, Robert A; Siddesha, Jalahalli M et al. (2012) CIKS (Act1 or TRAF3IP2) mediates Angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy. J Mol Cell Cardiol 53:113-24
Pisitkun, Prapaporn; Ha, Hye-Lin; Wang, Hongshan et al. (2012) Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis. Immunity 37:1104-15
Sønder, Søren Ulrik; Paun, Andrea; Ha, Hye-Lin et al. (2012) CIKS/Act1-mediated signaling by IL-17 cytokines in context: implications for how a CIKS gene variant may predispose to psoriasis. J Immunol 188:5906-14
Sonder, Soren Ulrik; Saret, Sun; Tang, Wanhu et al. (2011) IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J Biol Chem 286:12881-90
Pisitkun, Prapaporn; Claudio, Estefania; Ren, Nina et al. (2010) The adaptor protein CIKS/Act1 is necessary to induce collagen-induced arthritis pathology and it contributes to collagen-specific antibody production. Arthritis Rheum :
Claudio, Estefania; Sonder, Soren Ulrik; Saret, Sun et al. (2009) The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol 182:1617-30