Regulation of Gene Expression and Cell Proliferation by Hormones and Cytokines as Part of Homeostasis, Stress Response, Inflammation and Tumorigenesis
A network of cytokines, growth factors, hormones, and various biologically active metabolites control systemic homeostasis in the postnatal organism. Cytokines are major regulators of those evolutionarily conserved processes that determine, among others, the tissue response to injury, mediate inflammation, activate systemic acute phase reaction and fever, and direct the innate and adaptive immune responses. This laboratory pursues two long-term research programs. The first program has the overall goal of characterizing the cellular and molecular action of cytokines that mediated the local and systemic response to tissue damage and modulated tumor growth. The second program focuses on the genetics and biology of the hepatic acute phase response and the physiological role of the plasma proteins induced by inflammation.
Current work on the first program concerns the identification of the mechanisms by which members of the hematopoietic cytokine family control proliferation and expression of differentiation genes in various normal and transformed cell types. The studies address two questions: (1) What are the mechanisms by which the heteromeric receptors for the interleukin 6 class cytokines – namely IL-6, IL-31, leukemia inhibitory factor (LIF) and oncostatin M (OSM) – control cell proliferation and the expression of differentiated genes? And (2) how is the responsiveness to these IL-6 class cytokines controlled during malignant transformation of epithelial cells? The biochemical analysis of signaling employs various tissue culture cell lines in which the specific functions of the receptor subunits for the cytokines are reconstituted. The signaling action of the OSM receptor has been defined by the suppression of proliferation through mediating G1 arrest in part by the induction of cyclin kinase inhibitors and to trigger induction as well as suppression of genes through transcription factors that include STAT3 and STAT5, AP-1/ATFs, C/EBP and CREB. These cellular responses are used to characterize the structural motifs within the signal transducing receptor subunits (gp130, LIFR-alpha, OSMR-beta, IL-31R-alpha [or GPL]) that are required for engaging the intracellular signaling pathways, in particular leading to the activation of the JAKs, PI3K, and the MAPK pathways engaging ERK and JNK. Genetic targets through which the receptor signals induce transcription have been established in the examples of acute phase plasma protein genes in liver and other cell types. The cytokine-specific action determining the expression of intercellular adhesion molecules (ICAM), cytokines and chemokines in endothelial, stromal and epithelial cells as part of inflammation and fever response is identified in collaboration with members on the program for hyperthermia and photodynamic therapy. The altered profile of cytokine responses in cancer cell types compared to the normal counterparts has allowed the identification of changes in the expression of signaling proteins (as in the case of myeloid leukemias) and cytokine receptors (as in the case of lung epithelial cells) as function of malignant transformation. The tumor-specific expression of cytokine receptor subunits is in part correlated with epigenetic alterations in DNA methylation and histone acetylation. The information gain on inflammatory mediators and receptor functions in tissue culture model system are currently applied to the identification of regulatory processes in complex reconstituted systems using 3-dimensional cultures of primary cells isolated from the lung.
The work on the second program investigates how the acute phase response in various organs is controlled and what the physiological role of the acute phase proteins is. In the last few years, mouse models have been developed in which the expression of the major acute phase proteins, haptoglobin (hemoglobin binding protein), hemopexin (heme-binding protein) and alpha-1-acid glycoprotein (ligand-binding protein), are altered either by silencing through gene knockout or by overproduction through introducing constitutively expressed transgenes. These plasma proteins are effective regulators of three major processes associated with inflammation: inhibition of extracellular proteases, reduction of oxidative damages to tissue, and attenuation of the activity of inflammatory and immune cells. The recent studies on the biology of haptoglobin have focused on the anti-inflammatory function of this acute phase protein and its role in directing progression of tissue injury response, stimulated proliferation of tumor cells at site of inflammation, and directing the immune response through direct regulation of development of lymphoid organs and differentiation of lymphocytes. The hypothesis that inflammatory mediators are promoting proliferation of epithelial tumor cells is addressed by the effects of haptoglobin deficiency or overexpression in the intestinal tumor model provided by the Apc+/MIN mouse.