Interleukin-1 (IL-1), a major pro-inflammatory cytokine, has a wide range of biological activities in inflammation. The IL-1 receptor belongs to the IL-1R (IL-1 receptor)/TLR (Toll-like receptor) superfamily. Human TLRs have recently emerged as key components in the generation of immune and inflammatory responses due to their ability to recognize pathogen associated molecules. Much effort has been devoted towards the understanding of molecular mechanisms by which the IL-1R/TLRs mediate signaling, with the long-term objective to develop more effective anti-inflammatory small molecule drugs. While we are interested in the IL-1R/TLR signaling in general, this application focuses on the IL-1- mediated pathway, since the IL-1 pathway is likely to provide a """"""""prototype"""""""" for the similar yet distinct pathways mediated by TLRs. Genetic and biochemical studies revealed that IL-1R mediates a very complex pathway, involving a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription factor NFkappaB. Based on studies by our group and others, we have postulated a model for the IL- 1 pathway. Upon IL-1 stimulation, the IL-1 receptor mediates the formation of Complex 1, where IRAK4 (IL-1 receptor-associated kinase 4) is activated, leading to hyperphosphorylation of IRAK, which creates an interface for its interaction with adapter Pellino 1. The receptor proximal components are then released from the receptor to form an Intermediate Complex, followed by formation of Complex II, leading to phosphorylation of TAK1 (TGFbeta activated kinase, a MAP3K) and TAB2 (TAK1 binding protein 2) on the membrane. Complex III is then dissociated from Complex II and translocated from the membrane to the cytosol, where TAK1 is activated, followed by the activation of IKK (IkappaB kinase) and NFkappaB. While this model is well supported by the published studies and our preliminary data, the detailed molecular mechanisms for our model are largely lacking. The goal of this proposal is to elucidate the detailed molecular mechanisms for IL-1-induced receptor proximal signaling events, including formation and activation of the receptor complex (Aim 1), release of signaling components from the receptor (Aim 2), and translocation and activation of TAK1 (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM060020-06
Application #
6776871
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Marino, Pamela
Project Start
1999-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
6
Fiscal Year
2004
Total Cost
$321,300
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Pathology
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wan, Youzhong; Xiao, Hui; Affolter, Jeremy et al. (2009) Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. J Biol Chem 284:10367-75
Xiao, Hui; Qian, Wen; Staschke, Kirk et al. (2008) Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation. J Biol Chem 283:14654-64
Fraczek, Jerzy; Kim, Tae Whan; Xiao, Hui et al. (2008) The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation. J Biol Chem 283:31697-705
Johnson, Angela C; Li, Xiaoxia; Pearlman, Eric (2008) MyD88 functions as a negative regulator of TLR3/TRIF-induced corneal inflammation by inhibiting activation of c-Jun N-terminal kinase. J Biol Chem 283:3988-96
Li, Xiaoxia (2008) IRAK4 in TLR/IL-1R signaling: possible clinical applications. Eur J Immunol 38:614-8
Kim, Tae Whan; Staschke, Kirk; Bulek, Katarzyna et al. (2007) A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. J Exp Med 204:1025-36
Qin, Jinzhong; Jiang, Zhengfan; Qian, Youcun et al. (2004) IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J Biol Chem 279:26748-53
Li, X; Commane, M; Nie, H et al. (2000) Act1, an NF-kappa B-activating protein. Proc Natl Acad Sci U S A 97:10489-93