Molecular Signaling Events Controlling Innate Immunity and Inflammation

Research in my lab focuses on the signaling events controlling the innate immunity, infection, and inflammation. Alteration in innate immunity has been recognized to contribute to various human inflammatory diseases. A family of Toll-like receptor proteins recognize a diverse array of microbial as well as other cues and relay the signals through a serious of intracellular signaling components including the interleukin-1 receptor-associated kinase (IRAK) family proteins (1, 2, M, and 4). Each IRAK member has unique regulation and role in mediating innate immune response. We have demonstated that IRAK1 undergoes stimulus-dependent activation, sumoylation and nuclear translocation. In contrast to IRAK4 which plays a critical role in the canonical NFkB activation pathway, IRAK1 is not involved in the classical NFkB pathway. Rather, IRAK1 contributes to the regulation of several other downstream molecules such as IRF5/7 and STATs. IRAK-M, on the other hand, negatively regulates NFkB activation.

We are also interested in the examination of other signaling molecules involved in innate immunity such as Tollip. We have found that Tollip can specifically bind with phosphatidylinositol-3-phosphate, and such binding may be essential for its cellular function.

Future studies include detailed biochemical, molecular as well as functional studies of IRAK family kinases and other signaling molecules involved in innate immunity. In particular, we plan to determine the nature of IRAK1 modification and nuclear localization as well as identifying other cellular targets of IRAK1. The involvement of IRAK proteins in the pathogenesis of atherosclerosis and other inflammatory diseases are being examined using transgenic animal models.

Selected Publications:

For recent publications since 2002 click here.

Xie Q, Gan L, Wang J, Wilson I, Li L. (2007) Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth. Mol Immunol. 44:3453-3461.

Su J, Xie Q, Wilson I, Li L. (2007) Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling.Cell Signal. 19:1596-1601.

Lakoski SG, Li L, Langefeld CD, Liu Y, Howard TD, Brosnihan KB, Xu J, Bowden DW, Herrington DM. (2007) The association between innate immunity gene (IRAK1) and C-reactive protein in the Diabetes Heart Study. Exp Mol Pathol. 82:280-283.

Su J, Richter K, Zhang C, Gu Q, Li L. (2007) Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants.Mol Immunol.2007 Feb;44(5):900-5.

Gan L, Li L. (2006) Regulations and Roles of the Interleukin-1 Receptor Associated Kinases (IRAKs) In Innate and Adaptive Immunity. Immunologic Research. 2006;35(3):295-302.

Fasciano S, Li L. (2006) Intervention of Toll-like receptor-mediated human innate immunity and inflammation by synthetic compounds and naturally occurring products. Curr Med Chem. 13(12):1389-95.

Paulsen MT, Starks AM, Derheimer FA, Hanasoge S, Li L, Dixon JE, Ljungman M. (2006) The p53-targeting human phosphatase hCdc14A interacts with the Cdk1/cyclin B complex and is differentially expressed in human cancers. Mol Cancer. 2006 Jun 19;5:25.

Sun J, et. al. (2006) Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 15(3):480-5.

Li T, Hu J, Thomas J, and Li L. (2005) Differential regulation of apoptosis by LPS and taxol in THP-1 cells. Molecular Immunology. 42: 1049-1055.

Sun J, Zheng S, Chang B, Li L, Li G, Liu W, Turner AR, Meyers DA, Isaacs EB, Xu J, Grönberg H. (2005) Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) are associated with prostate cancer risk. Journal of the National Cancer Institute. 97: 525-532.

Chan C, Li L, McCall CE, Yoza B. (2005) Endotoxin Tolerance Disrupts Chromatin Remodeling and NF-B Transactivation at the IL-1 Promoter. Journal of Immunology . 175: 461-468.

Huang YS, Li T, Sane D, Li L. (2004) IRAK1 serves a novel regulator essential for IL-10 gene expression. J Biol Chem . 279:51697-51703.

Li T, Hu J, and Li L. (2004) Regulation of Tollip by lipopolysaccharide in THP-1 cells. Molecular Immunology. 41 (1):85-92.

Li L . (2004) Regulation of innate immunity signaling and its connection with human diseases. Current Drug targets-Inflammation & Allergy. 3: 81-86 .

Jacinto R, Hu J, Hartung T, McCall CE, Li L. (2002) LPS and LTA-induced tolerance and cross-tolerance: Distinct alterations in IRAK. Journal of Immunology. 168: 6136-6141.

Moors M, Li L, Mizel S. (2001) Bacterial FliC protein activates macrophages via TLR-IRAK mediated pathway. Infection and Immunity. 69, 4424-4429.

Learn C, Boger S, Li L, McCall CE. (2001) Phosphortidyl-inositol-3-phosphate kinase selectively controls IL-1 RA protein production in tolerant cells. J Biol Chem. 276, 20234-9.

Liwu Li , Jack Dixon. (2000) Form, function, and regulation of protein tyrosine phosphatases and their involvement in human diseases. Seminars in Immunology. 12 (1), 75-84.

Liwu Li , Sue Coursat, Jean Hu, Charles McCall. (2000) Characterization of Interleukin-1 receptor associated kinase in normal and tolerant cells. Journal of Biological Chemistry.275, 23340-45.