Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether levels of interleukin (IL)-18, together with those of IL-1beta, tumor necrosis factor-alpha, IL-6, and IL-8, are elevated in the plasma of patients with gouty arthritis, the plasma concentrations of those cytokines were measured in 31 males with gouty arthritis. Further, CD14+ cells were obtained from human blood and thioglycolate medium-induced peritoneal cells obtained from caspase 1-deficient mice, and then separately cultured in the presence of monosodium urate monohydrate (MSU) crystals. In addition, in an animal in vivo experiment, MSU crystals were injected into subcutaneous air pouches of IL-18-deficient mice. The plasma concentrations of IL-18, IL-6, and IL-8 were elevated in the presence of gouty arthritis in the gout patients. In the in vitro study, the presence of MSU crystals stimulated CD14+ cells (monocytes) to secrete IL-18 and increased the activity of caspase 1 in CD14+ cells, whereas there was no significant effect on IL-18 messenger RNA in CD14+ cells and only a slight induction of IL-18 secretion from thioglycolate medium-induced caspase 1-deficient peritoneal cells. In the in vivo experiment, MSU crystals injected into the air pouch promoted neutrophil accumulation along with an increase in concentrations of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha in air-pouch fluids in both IL-18-deficient and wild-type mice. However, there was no increase in the concentration of IL-18 in air-pouch fluids in either mouse strain. Our results suggest that plasma IL-18, IL-6, IL-8, and C-reactive protein (CRP) levels reflect local inflammation associated with gouty arthritis, though IL-18 does not play an important role in neutrophil accumulation. Further, they suggest that MSU crystals accelerate the processing of IL-18 from an inactive to active form via the activation of caspase 1.
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PMID:Plasma interleukin (IL)-18 (interferon-gamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. 1640 56

The Ah receptor (AHR) has been shown to exhibit both inflammatory and anti-inflammatory activity in a context-specific manner. In vivo macrophage-driven acute inflammation models were utilized here to test whether the selective Ah receptor modulator 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce inflammation. Exposure to SGA360 was capable of significantly inhibiting lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms of lethality and attenuating inflammatory signaling in tissues. Topical exposure to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU) crystal gout mouse model. Inhibition was dependent on the expression of the high-affinity allelic AHR variant in both acute inflammation models. Upon peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360 attenuated the expression of numerous inflammatory genes and genes known to be directly regulated by AHR in thioglycolate-elicited primary peritoneal macrophages treated with LPS. In addition, expression of the high-affinity allelic AHR variant in cultured macrophages was necessary for SGA360-mediated repression of inflammatory gene expression. Mechanistic studies revealed that SGA360 failed to induce nuclear translocation of the AHR and actually enhanced cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR ligand activity was detected in peritoneal exudates isolated from MSU-treated mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated at least in part through AHR antagonism of endogenous agonist activity. These results underscore an important role of the AHR in participating in acute inflammatory signaling and warrants further investigations into possible clinical applications.
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PMID:Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses. 2889 97