Youhai H. Chen, M.D., Ph.D.
Professor, Pathology and Laboratory Medicine

Gene Therapy and Vaccines Program

Lab Address

711 Stellar Chance Laboratories
422 Curie Blvd.
Philadelphia, PA 19104-6160

Phone:215 898 4671
Fax: 215 573 3434
E-mail:yhc@mail.med.upenn.edu

Shandong Medical University, Jinan, Shandong: MD, 1978-1986.

University of Manitoba, Winnipeg, Manitoba: PhD (Immunology), 1988-1993.

Harvard Medical School, Boston, Massachusetts: Postdoctoral Research (Immunology), 1993-1995.

Research Interests

• Autoimmunity, Innate Immunity, and Gene Therapy.

Key words: Gene therapy, genomics, autoimmune diseases, TLR, innate immunity, immunologic tolerance, apoptosis, and therapeutics

Description of Research

I. Genes and Genomics of Autoimmune Inflammation. The major goals of Dr. Chen’s research program are to understand the molecular mechanisms of autoimmune diseases (such as multiple sclerosis and type 1 diabetes) and to find a cure for these diseases. Although the etiological factors that trigger these diseases vary, the common pathological outcome of autoimmune diseases is the destruction of self-tissues by activated lymphoid and myeloid cells through a process called autoimmune inflammation. Development of autoimmune inflammation requires coordinated expression of myriad genes that mediate the activation, migration and effector functions of inflammatory cells. These include genes that encode antigen receptors, costimulatory molecules, cytokines, chemokines, and cytotoxic enzymes. To explore the spectrum and global patterns of gene expression during autoimmune inflammation, Dr. Chen’s laboratory has recently performed functional genomic studies of autoimmune inflammation in the central nervous system (CNS). Inflammation in the CNS not only induced the expression of many immune-related genes, but also significantly altered the gene expression profile of neural cells. A number of unique clusters of genes were identified which represent putative immune and nervous responses in autoimmune inflammation. Using models of inflammation, Dr. Chen and colleagues are exploring the physiological and pathological roles of the following genes: the Rel/nuclear factor (NF)-κB family, Bim and TRAIL. The following questions are being examined: 1) What are the roles of these genes in the activation and effector function of inflammatory cells following antigen or Toll-like receptor activation? 2) What are the roles of these genes in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells?

II. Negative Regulation of Toll-like Receptor Signaling. Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. However, over-activation of TLRs can lead to deleterious inflammatory diseases. Dr. Chen and colleagues have recently found that B cell leukemia (Bcl)-3 plays an essential role in limiting TLR activation. By blocking ubiquitination of NF-κB p50, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3-deficient mice and cells are hypersensitive to TLR activation and unable to control responses to lipopolysacchrides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR response and maintains innate immune homeostasis. The molecular mechanisms through which p50 ubiquitination is regulated by Bcl-3 are the focus of the current investigation.

III. Apoptosis and immune homeostasis. Immune homeostasis is essential for the normal functioning of the immune system and its breakdown leads to fatal inflammatory diseases. Dr. Chen’s laboratory has recently cloned a novel member of the tumor necrosis factor-α-induced protein-8 family, designated TIPE2 (TNFAIP8L2) that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues and its deletion in mice leads to multi-organ inflammation, splenomegaly and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor and T cell receptor signaling. Importantly, TIPE2 binds to caspase-8, and inhibits activating protein-1 and nuclear factor-κB activation while promoting death receptor-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. Thus, TIPE2 is a novel negative regulator of TLR and TCR signaling, and its selective expression in the immune system prevents hyper-responsiveness and maintains immune homeostasis. Dr. Chen and colleagues are investigating the molecular mechanisms of TIPE2 action in innate and adaptive immunity.

IV. Gene therapy. Using apoptosis-inducing genes such as FasL and TRAIL, Dr. Chen and colleagues are exploring the potential of apoptosis-based gene therapy for the treatment of autoimmune diseases. One of the current projects is to determine which molecular pathway(s) is responsible for the therapeutic effect of TRAIL in inflammatory diseases.

Selected Publications

Hilliard, B., N. Mason, L. Xu, J. Sun, S-E. Lamhamedi-Cherradi, H-C Liou, C. Hunter, and Y. H. Chen. Critical Roles of c-Rel in Autoimmune Inflammation and Helper T Cell Differentiation. Journal of Clinical Investigation 110:843-850, 2002.

Lamhamedi-Cherradi, S-E., S. Zheng, K. Maguschak, J. Peschon, Y. H. Chen. Defective Thymocyte Apoptosis and Accelerated Autoimmune Diseases in TRAIL-/- Mice. Nature Immunology 4(3):255-260, 2003.

Zheng, S., P. Wang, Y. H. Chen. Critical roles of TRAIL in hepatic cell death and hepatic inflammation. Journal of Clinical Investigation 113:58-64, 2004.

Carmody, R.J., Q. Ruan, S. Palmer, B. Hilliard, Y. H. Chen. Negative regulation of Toll-like receptor signaling by NF-κB p50 ubiquitination blockade. Science 317: 675-678, 2007, 2007.

Sun, H., S. Gong, R. J. Carmody, A. Hilliard, L. Li, J. Sun, L. Xu, B. Hilliard, S. Hu, H. Shen, X. Yang, and Y. H. Chen. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133: 415-426, 2008.

Search PubMed for more articles

Lab

Rotation Projects

1. To determine the roles of NF-κB and TIPE2 in the activation and effector function of inflammatory cells.
2. To determine the roles of NF-κB and TIPE2 in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells.
3. To characterize the TIPE2 signaling pathway.
4. To define the NF-κB network in T cells and myeloid cells using functional genomic tools such as ChIP-on-chip and ChIP-SAGE.

Lab personnel

Carcillo, Marla, B.A., Administrative Assistant
Carmody, Ruaidhri, Ph.D, Senior Research Investigator
Chen, Youhai, MD, Ph.D, Professor
DeVirgiliis, Jennifer, B.A., Research Specialist
Gong, Shunyou, MD, Ph.D Senior, Research Investigator
Johnson, Derek, B. Sc. Ph.D., Student
Kameswaran, Vasumathi, B. Sc., Student
Kong, Li, MD, Visiting Scholar
Li, Li, MD, Ph.D, Post-Doctoral Researcher
Ludwinski, Maciej, M.Sc., Ph.D. Student
Mooney, Erin, Student
Palmer, Scott, B. Sc., Ph.D. Student
Ruan, Qingguo, Ph.D, Post-Doctorial Researcher
Xue, Fan, Ph.D, Post-Doctorial Researcher