Receptor-mediated inflammatory response

TNF-a and IL-1 are current targets of antiinflammatory drug therapy. A homotrimer of 17-kDa protein subunits whose effects include the activation of neutrophils and eosinophils, induction of COX-2, induction of proinflammatory cytokines (e.g., IL-1, IL-6), enhancement of endothelial layer permeabihty, induction of adhesion molecules by endothelial cells and leukocytes, stimulation of fibroblast proliferation, degradation of cartilage, and stimulation of bone reabsorption. Two receptors mediate these effects a 55-kDa receptor (p55) and a 75-kDa receptor (p75). Each of these receptors is found in both cell surface and soluble forms. The binding of two or three cell surface receptors to TNF-a initiates an inflammatory response. Soluble p55 also acts as a signaling receptor for inflammatory responses, whereas soluble p75 acts as an antagonist. 

Bhattacharyya S, Brown DE, Brewer JA, Vogt SK, Muglia LJ. Macrophage glucocorticoid receptors regulate Toll-like receptor-4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 2007, 109, 4313M319. 

Ciclosporin oU-in-water emulsion has been used in the local treatment of moderate to severe dry eye disease. Chronic dry eye disease results from inflammation mediated by cytokines and receptors for autoimmune antibodies in the lacrimal glands. It affects the lacrimal gland acini and ducts, leading to abnormahties in the tear film, and ultimately disrupting the homeostasis of the ocular surface. Topical ciclosporin reduces the cell-mediated inflammatory response associated with inflammatory ocular surface diseases. 

It has been well characterized that the functional interaction between macrophages and neutrophils is critical for mediating inflammatory response to tissue injury (Figure 2). Tissue macrophages express a wide array of receptors for the recognition of PAMPs and DAMPs, which include Toll-like receptors, NOD-like receptors (NLRs), and scavenger receptors [20]. After initial recognition of a... 

BK actions are mediated through at least two types of GPCR B and B2. At the B receptor, des-Arg BK is more potent than BK. The converse is tme at the B2 receptor. The effects of BK are primarily mediated by activation of the B2 receptor because the B receptor has limited tissue distribution and is iaduced by noxious stimuli such as apamin or an inflammatory mediator-type response. The existence of a B receptor was suggested on the basis of limited efficacy of known antagonists ia some systems. A B receptor may also exist. The human B2 receptor has been cloned. 

While the findings in mice are of interest, it is important to note that there are four known mammalian adenosine receptors and that the pattern of adenosine receptor expression on mast cells (as well as other immime cells and/or structural cells), and the regulation of their expression by such cells (e.g., during inflammatory responses), which can represent major determinants of adenosine responses, vary substantially among species [70-72]. For example, it is thought that adenosine-induced broncho-constriction is mediated by adenosine A1 and A2B receptors in rats and mice, A3 receptors in rats, guinea-pigs and mice, and A2B receptors in humans [72]. 

Fig. 11.1. Atherogenesis is a persistent inflammatory response that occurs in response to conditions that cause endothelial damage (e.g., hypercholesterolemia and oxLDL). After endothelial cells are activated, they elaborate cytokines, chemokines, and other mediators that recruit mononuclear cells (monocytes and T lymphocytes) to extravasate into the vessel wall where they are activated and release additional proinflammatory factors. Macrophages are able to take up oxLDL via scavenger receptors causing them to differentiate into foam cells and form a fatty streak that progresses to an atheroma with a necrotic lipid core and a fibrous cap. Chemokines can lead to weakening of the fibrous cap and eventual plaque rupture leading to thrombosis and occlusion of the involved vessel.

Fig. 14.1. The Thl/Th2 balance is central to the regulation of normal wound repair. Tissue injury results in the initiation of an inflammatory response, mediated by a variety of cells and their by-products. Immune cells are recruited and cross-regulate the Thl/ Th2 balance that occurs in response to the cytokine environment. This balance is in turn cross-regulated by the chemokine/chemokine-receptor expression profile, which functions to amplify the inflammatory process. Cells residing in the injured tissue release profibrotic mediators, which promote fibroblast activation, proliferation, and differentiation to the myofibroblast phenotype. Myofibroblasts produce collagen to repair damaged tissue, which is an event that is favored by the inhibition of MMP activity. The Thl/Th2 balance is central to whether a normal or aberrant wound-repair process is established A Thl environment promotes normal tissue resolution (fibrinolysis), whereas a Th2 environment maintains the progression of fibrotic disease (excessive collagen deposition).

Examples of the class of receptors that recruit nonreceptor PTKs include those that mediate immune and inflammatory responses ... 

---