Growth factors and cytokines

Elevated peripheral arterial resistance is a hallmark of primary hypertension. The increase in peripheral resistance typically observed may be due to a reduction in the arterial lumen size as a result of vascular remodeling. This remodeling, or change in vascular tone, may be modulated by various endothelium-derived vasoactive substances, growth factors, and cytokines. This increase in arterial stiffness or reduced compliance results in the observed increase in systolic blood pressure.9... 

Leaman, D.W., Leung, S., Li, X., and Stark, G.R. 1996. Regulation of stat-dependent pathways by growth factors and cytokines. FASEB Journal 10(14), 1578-1588. 

Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC (1998) Osteoblast programmed cell death (apoptosis) modulation by growth factors and cytokines. J Bone Miner Res 13 793-802... 

Alexander, J., Samples, J., and Acott, T., Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression, Curr. Eye Res., 17, 276, 1998. 

As would be expected of active protein secreting cells, glandular epithelial tissue, the cytokine secreting cells of the immune system and the blood vessel endothelium, have an extensive internal structure consisting of rough endoplasmic reticulum and numerous mitochondria. Peptide hormones, growth factors and cytokines like all proteins are synthesized by DNA transcription and mRNA translation. The primary transcript of the mRNA may code for an inactive prohormone which requires careful proteolysis to produce the active hormone, as for example in the case of insulin. Adrenocorticotropic hormone (ACTH) is particularly interesting in this respect because... 

Coroneos, E., Martinez, M., McKenna, S. and Kester, M., 1995, Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation./.B/oZ.Clrem. 270 23305-23309. 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

Insulins (see p. 388), growth factors, and cytokines (see p. 392), for example, act via 1-helix receptors. Binding of the signaling substance leads to activation of internal kinase activity (in some cases, dimerization of the receptor is needed for this). The activated kinase phosphorylates itself using ATP (auto-phosphorylation), and also phosphorylates tyrosine residues of other proteins (known as receptor substrates). Adaptor proteins that recognize the phosphotyrosine residues bind to the phosphorylated proteins (see pp. 388, 392). They pass the signal on to other protein kinases. 

The number of cells in any tissue is mainly regulated by two processes—cell proliferation and physiological cell death, apoptosis. Both of these processes are regulated by stimulatory and inhibitory factors that act in solute form (growth factors and cytokines) or are presented in bound form on the surface of neighboring cells (see below). 

Ligands such as growth factors and cytokines, which promote cell proliferation. 

Another important family of kinases for drug discovery is the mitogen-activated protein kinases (MAPKs). These are proline-directed serine/threonine kinases that activate their substrates by dual-phosphorylation. MAPK enzymes are activated by a variety of signals including growth factors and cytokines, discussed in chapter 6. The MAPK family plays a critical role in cell cycle progression. Small molecule inhibitors of MAPK may have utility in the treatment of cancer. 

The expression of the ET-1 gene is increased by growth factors and cytokines, including transforming growth factor-B (TGF-B) and interleukin 1 (IL-1), vasoactive substances including Ang II and vasopressin, and mechanical stress. Expression is inhibited by nitric oxide, prostacyclin, and ANP. 

As some of the newer drugs such as hormones, growth factors, and cytokines now being produced are peptides and certain toxins are also peptides or proteins, the role of peptidases may be important. Peptidases are especially active in the lumen of the gut, and consequently many such drugs are administered intravenously. Also some natural protein toxins may bypass the gut by via bites or stings into tissue. However, peptidase activity is also found in blood and other tissues. Peptidases are also important in the further metabolism of glutathione conjugates (see below). 

The atherosclerotic lesions develop in a complex, chronic process. The first detectable lesion is the so-called fatty streak, an aggregation of lipid-laden macrophage foam cells. The next stage of development is the formation of plaques consisting of a core of lipid and necrotic cell debris covered by a layer of connective tissue and smooth muscle cells. These plaques hinder arterial blood flow and may precipitate clinical events by plaque rupture and thrombus formation. Platelets from the thrombi, activated macrophages, and smooth muscle cells release growth factors and cytokines resulting in an inflammatory-fibroproliferative response that leads to the advanced lesions of atherosclerosis. 

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