Tumor necrosis factor gene expression response

Corticosteroids suppress both humoral and cellular immunity. Single doses produce a redistribution of lymphocytes with a concentration dependent decrease of CD4 and CDS positive cells. This in vivo lymphopenic effect correlates with the in vitro inhibition of stimulated T-cell proliferation. Furthermore, corticosteroids are able to inhibit the expression of genes coding for IL-1, IL-2, IL-6, interferon a, and tumor necrosis factor, TNE-a. Chronic administration decreases the size and also the cellu-larity of lymphoid tissues like lymph nodes, spleen, and thymus. Corticosteroids have more effect on the primary immune response and are less effective against previously sensitized immune responses. Their suppressive effects are more pronounced for T-cell immune responses than for the humoral immune response. 

Lipids A first induce the expression of early inflammatory genes such as tumor necrosis factor- (TNF)-a, EL-1(3, type 2 TNF receptor, IP-10, D3, D8 and D2 genes [34]. Then further genes are activated such as other cytokines and receptors, adhesion molecules, acute-phase proteins, tissue factors, as well as the inducible NOS (NOS II). These cascades of events initiated by lipid A provoke in their target cells complex responses in vivo, whose relevance in the host response to tumor growth is reviewed below. 

In turn, MAPKs are also involved in the regulation of the gene expression of all three NOS isoenzymes. The expression of iNOS (NOS-2) is regulated by all three MAP kinase pathways in a variety of cell types [125-129]. For example, INK and ERKl/2 pathways are necessary for lipopolysaccharide (LPS-) and interferon-y-stimulated iNOS expression in mouse macrophage cells, possibly via a-tumor necrosis factor secretion, whereas p38 inhibited induction [130]. The induction of endothelial NOS (eNOS, NOS-3) by estrogen, fibroblast growth factor, or epidermal growth factor in endothelial cells involves the Ras-ERK pathway [131,132]. eNOS is phosphorylated, and thus activated, by the serine/threonine protein kinase Akt, which is recruited to the cell membrane by PI3-kinase as an antiapoptotic mechanism in the response of endothelial cells to shear stress [133]. 

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