Proinflammatory activity

Rheumatoid Arthritis. Figure 2 The concept of a cytokine dysequilibrium. Many cytokines are detectable in rheumatoid synovial tissues, including those with predominantly anti-inflammatory properties. But the net effect is a dominance of proinflammatory activity. 

Numerous and diverse biological functions are regulated by chemokines. In addition to the well characterized proinflammatory activities such as integrin activation, chemotaxis, lipid mediator biosynthesis, superoxide radical production, and granule enzyme release (reviewed in refs. 1-4), chemokines have been shown to suppress and stimulate angiogenesis (5-7), suppress hematopoiesis (8-10), suppress apoptosis (11), control viral infection (12,13), and effect leukocyte differentiation (14). Among the proinflammatory activities, chemotaxis in particular has received considerable attention as a target for novel antiinflammatory therapeutics (reviewed in ref. 15). 

Being an anaphylatoxin, however, C5a also expresses many proinflammatory activities. These include its potent chemotactic activities for the recruitment of inflammatory cells to sites of tissue injury and infection (Shin et al., 1968), its ability to induce smooth muscle contraction (Hugh et al., 1987), increase vascular permeability (Hugh and Muher-Eberhard, 1978 Hugh, 1981, 1990), and induce the release of a variety of secondary inflammatory mediators such as histamine, lysosomal enzymes, and vasoacdve eicosanoids from responsive cells such as mast cells, neutrophils, eosinophils, and macrophages (Drapeau etal., 1993 Johnson et al., 1975 Goldstein and Weissmann, 1974 Schorlemmer et al., 1976 Lundberg et al., 1987). 

Delineation of the role of a specific mediator in the bronchomotor response to a proinflammatory stimulus is usually obtained by the ability of a specific receptor antagonist to block the response. This process of identification is dependent on the antagonist s being applied in doses sufficient to block the receptor for the endogenously released mediator and selective for the receptor of the mediator at the applied doses. Specific antagonists have been developed or are currently being developed for many of the inflammatory cell-derived mediators possessing bronchoconstrictor or proinflammatory activity. 

Purified GPIs, obtained by proteinase K digestion from the mucins of T. cruzi trypomastigotes (tGPIs), are potent inducers of nitric oxide, tumor necrosis factor-a and interleukin-12. The unsaturated fatty acid of the GPI alkylacyl-PI moiety is essential for bioactivity, but other features of the intact GPI are also necessary since the PI obtained by nitrous acid treatment was inactive.32 Correlation between GPI structure and proinflammatory activity in macrophages has been reviewed.52... 

I. C. Almeida and R. T. Gazzinelli, Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi. structural and functional analyses,. /. Leukoc. Biol., 70 (2001) 467-477. 

Lee C, Barnett J, Reaven PD (1998) Liposomes emiched in oleic acid are less susceptible to oxidation and have less proinflammatory activity when exposed to oxidizing conditions. J Lipid Res 39 1239-1247... 

Lins, K.O.A.L., Vale, M.L., Ribeiro, R.A., Costa-Lotufo, L.V., 2012. Proinflammatory activity of an alginate isolated from Sargassum vulgare. Carbohydr. Polym. 92,414—420. 

GPI fraction purified from T. cruzi trypomastigote mucins has a level of proin-flammatory activity that is comparable with bacterial hpopolysaccharide [9]. Given that neither the glycan structure alone nor the lyso-aUcyl- or acyl-alkyl-phosphatidylinositol moieties are able to induce the production of NO, interleukin 12 (IL-12), and tumor necrosis factor-a (TNF-a) in macrophages, it is hypothesized that the full GPI structure, containing the unsaturated fatty acids, is necessary for the observed proinflammatory activity. 

The complement system consists of circulating plasma proteins that, upon activation, exhibit enzymatic and proinflammatory activities [174]. Two components of this system are important to the inflammatory process, complement factors C3a and C5a. Both peptides stimulate mast cells to release histamine and PAF (cf. below). In addition to these activities. 

It was proved that the absorption process of the MCFAs did not affect the basal secretion of the IL-8 in the intestine cells in comparison with LCFAs, results of clinical importance in the maintenance of the intestinal inflammation (Andoh et al., 2000). The replacement of dietary LCT with MCT is a good strategy for CD patients because MCTs decrease the proinflammatory activity and because they reduce both steatorrhea and diarrhea as well as fecal electrolyte excretion in patients with a reduced small intestinal mucosal area (Andoh et al., 2000 Jeppensen and Mortensen 1998). 

Three TLR9 agonists that induce distinct immune response profiles based on their structures have been selected for clinical studies. lMO-2055 is a lead clinical candidate for the treatment of cancers. The safety and pharmacodynamic activity of lMO-2055 have been studied in Phase-1 rising-dose trials in healthy and cancer subjects. A dose-dependent transient migration of lymphocytes from peripheral blood, activation of surface markers on immune cells, and elevation of plasma cytokines has been observed, consistent with immune-stimulatoiy activity of IMO-2055. No significant acute phase or proinflammatory activity, including no effects on cortisol, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were observed [41, 115-118]. 

In general, the eicosanoids derived from AA have potent prothrombotic and proinflammatory activity. In contrast, the eicosanoids derived from EPA have reduced biological activity and are less prothrombotic and proinflammatory. Eicosanoid production is generally tightly controlled through homeostatic mechanisms. However, eicosanoid production can be significantly altered in situations in which endothelial dysfunction, atherosclerosis and plaque rupture, or various thrombotic or inflammatory conditions are present. 

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