LPS-induced TNFa production

Phomopsis sp. 22502, the structures of which are shown in Figure 6. The first of these to be identified was XR379, a novel (65)-4,6-dimethyldodeca-2 ,4 -dienoyl ester of a prop-2 -enoic side chain-bearing analogue of the known frmgal metabolite phomalactone. This inhibited LPS-induced TNFa production by U937 cells with an IC50 of 2pM. 

Probucol, a hypocholesterolemic drug that possesses antioxidant activity, inhibits the ex vivo release of IL-1 from LPS-stimulated macrophages of mice pretreated orally with 100 mg/kg/day of this compound [94,95]. This compound has been shown to inhibit LPS-induced zinc-lowering effect, is cited as direct evidence for the inhibition of IL-1 release, and may be useful candidate for the treatment of atherosclerosis [95,96]. An amino-dithiol-one derivative (RP 54745) blocked the proliferative action of IL-1 P on murine thymocytes in vitro and also inhibited the production of IL-1 in mouse peritoneal macrophages in vitro and in vivo. The compound RP 54745 selectively inhibited the expression of IL-la and IL-1 3 mRNA while TNFa mRNA was unaffected [97, 98]. 

NO ( 3) [LPS-induced macrophage NO production] 4- NO [blocks macrophage LPS-induced NO blocks D-Galactosamine/ TNFa-induced hepatotoxicity hepatoprotective]... 

PLA2 [inhibits LPS-induced COX-2, iNOS TNFa production]... 

Edema toxin does not produce major tissue damage. In fact, its major role is to impair phagocyte function (Leppla, 2000). This is consistent with other toxins which fimction to elevate cAMP concentrations. Edema toxin inhibits phagocytosis of spores by human PMNs (O Brien et al, 1985) similar to LF this is in contrast to spores which promote immune cell uptake (see Table 31.1). Increased intracellular cAMP induced by EF inhibits neutrophil chemotaxis, phagocytosis, superoxide production, and microbicidal activity (Crawford et al, 2006 Turk, 2007 O Brien et al, 1985 Friedman et al, 1987 O Dowd et al, 2004 Ahmed et al, 1995). EF has been shown to inhibit TNFa and increase IL-6 production (Hoover et al, 1994). Increased cAMP levels also block LPS-induced activation... 

IL-7 is known to regulate HIV-1 replication in naturally infected peripheral blood mononuclear cells (PBMCs). From asymptomatic, chronically infected donors, IL-7-induced virus rephcation and increased proviral DNA levels in these ceEs are probably independent of the stimulation of IL-lp, IL-6, or TNFa production by PBMCs. 

Cytokine Production/Cellular Activation TNFa and IFNy mediate the induction of other cytokines (IL-1 and IL-6) and the activation of phagocytes. It has been suggested that particle-induced expression of MIP-2 and cytokine-induced neutrophil chemoattractant CKs in the rat lung are mediated at least in part by production of TNFa. TNF is involved in control of monocyte-mediated regulation of cytokine production by T cells. Preincubation of monocytes with rTNF enhanced their ability to induce IFNy production, and TNF synthesis inhibitors decreased this induction. However, Th2 cells are stimulated in the relative absence of monocyte co-stimulatory signal(s), probably IL-6. Concerning pain responsivity, TNFa produces dose-dependent hyperalgesia mediated via the induced release of IL-lp. ... 

Cat s claw (Uncaria tomentosa and Uncaria guianensis), an herbal medicine from the Amazon, is widely used to treat inflammatory disorders. Both species of cat s claw provide effective antioxidant and anti-inflammatory activities, but Uncaria guianensis is the more potent of the two. Non-alkaloid fractions from both species have been found to decrease lipopolysaccharide (LPS)-induced TNF-a and nitrite production in RAW 264.7 cells, and oral pretreatment for 3 days with Uncaria tomentosa actually prevented TNFa mRNA expression and apoptosis. Interestingly, the pharmacological properties of these species do not seem to be dependent on the presence of oxindole or pentacyclic alkaloids [191]. 

IL-10 and IL-4 inhibit cytoldne expression in activated human monocytes, which suggests that IL-4 may inhibit the transcription of the IL-6 gene. IL-10 may inhibit the IL-6 mRNA levels posttranscriptionally, without suppressing promoter activity in human monocytes.IL-10 also inhibits the production of IL-6, IL-12, and TNFa." Reduced IL-6 levels in individuals who are exposed to chromate were reported, pointing to its possible role in negative immunomodulation. Also, nitrite (NO ) induces a decrease of LPS-stimulated IL-1 (3, IL-6, IL-8, and TNFa release from activated alveolar macrophages. ... 

A number of cytokines have been implicated as endogenous pyrogens, including IL-1, TNFa, interferon-y, IFN-y, IFNa, IL-8, and IL-6, with IL-1 and IL-6 being the most potent (B68, R27). Since IL-ip will induce IL-6 production and circulating levels of IL-lp appear not to be sufficient to account for fever, it is possible that IL-6 alone or stimulated by low concentrations of IL-ip is the endogenous pyrogen (L14). 

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