Inhibition and prevention of monosodium urate monohydrate crystal–induced acute inflammation in vivo by transforming growth factor β1

Abstract

Objective. We investigated the effects of transforming growth factor Pl (TGFP1) on monosodium urate monohydrate (MSU) crystal-induced acute inflammation in vivo.Methods. One hour after MSU crystal-induced acute inflammation was produced in the rat subcutaneous air pouch model, the effects of recombinant human TGFPl (rHuTGFP1; 10-100 pglanimal) and ultrapure TGFPl (UPTGFPI; 100 and 500 pglanimal) were assessed, based on absolute and differential white blood cell counts in the exudate. The effects of 10 pg of rHuTGFP1 preincubated with a specific anti-TGFP antibody, and the effects of coinjection of crystals and rHuTGFP1, were also studied.Results. UPTGFPl and rHuTGFPl markedly reduced MSU crystal-induced inflammation. Recombinant human TGFPl also reduced inflammation when administered concomitantly with MSU crystals. Moreover, rHuTGFPl and UPTGFP1, injected l hour after MSU crystal injection, reduced the inflammatory response in a dose-dependent manner. Injection of rHuTGFPl (100 pglanimal) resulted in a >9w0 reduction in the maximal white blood cell count, achieved 6 hours after Spontaneous resolution is an important clinical feature of gouty attacks that is not yet fully understood (1,2). Lowering of pH and stimulation of phagocyte oxidative metabolism during crystal-induced inflammation may promote monosodium urate monohydrate (MSU) crystal dissolution. However, this cannot entirely explain the self-limited nature of gouty inflammation, since MSU crystals can remain in the synovial fluid after acute inflammation and have been identified in noninflammatory synovial fluids from gout patients (3).In vitro (4) and in vivo ( 5 ) studies have shown that changes in the protein coating of MSU crystals and in other as-yet-unidentified components that are generated locally during subsiding inflammation probably contribute to the self-limited nature of acute gouty arthritis (6). There is strong in vitro evidence that proinflammatory cytokines such as interleukin-lP (ILlP), tumor necrosis factor P (TNFP), IL-6, and IL-8 (7-1 1) are released within hours when monocytes and macrophages are incubated with MSU crystals. Natural cytokine inhibitors such as IL-1 receptor antagonist (IL-1Ra) and/or soluble TNFa receptor, or other regulatory cytokines such as IL-4 and IL-10, may block acute and subsequent chronic inflammation.

Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air‐pouch model of acute gouty arthritis

“…All of these chemokines had previously been shown to play a role in neutrophil migration in the air-pouch model in response to both TNF␣ and SEA (39,40). The air-pouch model was selected since it has been used extensively in the past as a model of the synovial environment to study the mechanism of inflammation induced by different proinflammatory factors, including MSU (45)(46)(47)(48)(49)(50)(51). Designed to replicate the synovial lining, this model allows for the identification and study of emigrated leukocytes and molecules produced during an inflammatory response, although several features of the synovial environment are missing in air-pouch fibroblasts (52,53).…”

Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

“…Therefore, it has been postulated that monocytes elicit a proinflammatory response following MSU crystal stimulation, while M (e.g., differentiated recruited monocytes, resident synovial M) might clear MSU crystals without the induction of proinflammatory activity (12). Additionally, TGF-␤, an anti-inflammatory cytokine, was shown to inhibit MSU crystal-induced inflammation in vivo (45). Thus, the release of anti-inflammatory mediators by M might also contribute to down-regulate the acute gout attack.…”

Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

“…Release of the neutrophilexpressed calgranulin heterodimer S100A8/A9, one of the most abundant protein constituents of the neutrophil cytoplasm (12), appears to substantially amplify neutrophil recruitment in gouty inflammation (13). Importantly, the state of macrophage differentiation is a major factor in the uptake of MSU crystals and sequelae, including the capacity to express transforming growth factor ␤1 (TGF␤1), a native suppressor of experimental gouty inflammation (14)(15)(16).…”