Cytokines and Growth Factors in Autoimmune Diseases

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Cytokines and growth factors play critical roles in normal homeostasis of immune functions. TGF-'1 is the dominant negative regulator of inflammatory responses. We have earlier generated TGF-'1 null mice that exhibit multifocal inflammation associated with increased adhesion of leukocytes to endothelium, aberrant expression of MHC class-I and -II antigens, and autoimmune manifestations similar to Sjogren syndrome. Moreover, depletion of CD8 cells ameliorated health status of TGF-'1 null mice. To delineate role of TGF-'1 in aberrant MHC expression, TGF-'1 null mice were generated in the MHC-I and MHC-II deficient backgrounds. TGF-'1 X MHC-I null mice exhibit increased longevity associated with reduced inflammation, diminished autoimmune manifestations and significantly elevated myelopoiesis. Although the TGF-'1 X MHC-II mice exhibited lack of inflammation and autoimmune response, they showed neonatal mortality associated with increased myelopoiesis and metaplasia. These results indicate a dominant role of TGF-'1 in leukocyte maturation and function. Macrophage migration inhibitory factor (MIF) is a major protein constituent of the anterior pituitary gland released into the bloodstream during endotoxemia. For many years, MIF had been thought to be a T cell product associated with delayed-type hypersensitivity reactions. The identification of MIF as a pituitary "stress" hormone provides an important link in the regulation of systemic inflammatory responses by CNS. Additionally, there is a compelling evidence that suggests a strong link between MIF and cell cycle suggesting MIF as an inhibitor in G0 phase. In order to delineate the precise role of MIF in vivo, we have initiated targeted recombination for the generation of MIF null mice. During the process of generating ES cell clones that have disrupted MIF gene we found abnormally recombined clones. Detailed analysis of these clones revealed specific sequence motifs that can affect the homologous recombination process. These motifs include short regions of homologous sequence identity that have been shown to promote DNA alignment, a preponderance of tetramers (5'-AAGG/TTCC 3'), topoisomerase I consensus sites, and AT-rich sequences that can promote DNA cleavage and recombination. A retrovirus-like sequence, intracisternal-A particle, is identified 2 kb upstream of the murine MIF gene. One of the recombinations occurred near the long terminal repeat of this IAP sequence. These sequence motifs may affect planned disruption of this genetic locus and their characterization will help to delineate the mechanism of recombination.