MOLECULAR MECHANISMS OF CYTOKINE GENE EXPRESSION AND THEIR IMMUNOLOGICAL ACTIVITIES IN AUTO- AND TUMOR-IMMUNITY
Interleukin-12 (IL-12) is a heterodimeric, proinflammatory cytokine produced by phagocytic cells and plays a critical role in the activation and function of antigen-presenting cells and effector lymphocytes during microbial infection. IL-23 is an IL-12 related cytokine that nevertheless plays a distinct role in Th17-associated immune activities. IL-10 is a homodimeric cytokine produced mainly by monocytes/macrophages, activated T and B lymphocytes. IL-10 has potent anti-inflammatory and immunosuppressive activities on myeloid cell functions while it also exerts immune stimulatory effects on B cells for proliferation, differentiation and antibody production. It is a pivotal homeostatic regulator of immune reactivity. The production of IL-12, IL-23 and IL-10 by phagocytic and antigen-presenting cells is regulated in opposite manners during innate and adaptive immune responses. The understanding of the molecular mechanisms controlling the gene expression of IL-12, IL-23 and IL-10 in interactions between exogenous pathogens, endogenous "danger signals" and the immune system is essential to efforts to develop therapeutic strategies for infectious, malignant and autoimmune diseases. We are currently investigating in the following areas:
I. Molecular mechanisms of pathogen/antigen-mediated regulation of IL-12, IL-23 and IL-10 gene expression in macrophages and dendritic cells.
II. Molecular mechanisms of the regulation of IL-12, IL-23 and IL-10 gene expression during phagocytosis of apoptotic cells by macrophages and dendritic cells.
III. Molecular mechanisms of the regulation of IL-12, IL-23 and IL-10 gene expression by the Crohn's disease-associated mutants of nucleotide-binding oligomerization domain 2 (Nod2) in experimental colitis.
IV. Identification and characterization of a novel B-lymphocyte derived soluble factor that inhibits IL-12 production by antigen-presenting cells and IL-12-mediated anti-tumor activity.