Recent evidence suggests that the transcription factor, PPARgamma, is an important negative regulator of inflammation. Because studies of murine adipocytes and macrophages implicate IFN-gamma, a key mediator of granuloma formation in sarcoidosis, as a PPARgamma antagonist, we investigated the relationship between PPARgamma and IFN-gamma in bronchoalveolar lavage (BAL) cells of sarcoidosis patients and healthy controls.
BAL cells were analyzed for PPARgamma and IFN-gamma mRNA expression by quantitative PCR and for PPARgamma protein by immunocytochemistry and western blotting.
In sarcoidosis patients with severe, treatment-requiring disease, IFN-gamma was strikingly elevated and PPARgamma gene expression was deficient. In contrast, PPARgamma expression of non-severe patients was comparable to control but was still accompanied by increased IFN-gamma. By confocal microscopy, nuclear PPARgamma protein was detectable in alveolar macrophages from non-severe patients unlike previous observations of severe patients. In vitro exposure of BAL cells or purified alveolar macrophages to IFN-gamma resulted in dose-dependent repression of PPARgamma mRNA in both sarcoidosis and controls. IFN-gamma treatment also reduced PPARgamma protein in BAL lysates and nuclear PPARgamma content in control alveolar macrophages, resulting in a diffuse cytoplasmic PPARgamma distribution similar to that observed in severe sarcoidosis.
These novel results indicate that IFN-gamma represses PPARgamma in human alveolar macrophages but that in sarcoidosis, PPARgamma rather than IFN-gamma levels correlate best with disease severity. Data also emphasize the complex nature of PPARgamma restorative mechanisms in alveolar macrophages exposed to an inflammatory environment containing IFN-gamma -- a potential PPARgamma antagonist.
"Thus it is possible that IFN-γ and osteopontin may interact in a positive feedback loop to maintain high levels in untreated PPARγ KO mice. In human sarcoidosis, both osteopontin and IFN-γ are prominent in granulomas [24,25] and IFN-γ is persistently elevated in sarcoidosis BAL cells [26-28]. "
[Show abstract][Hide abstract] ABSTRACT: Background
Although granulomatous inflammation is a central feature of many disease processes, cellular mechanisms of granuloma formation and persistence are poorly understood. Carbon nanoparticles, which can be products of manufacture or the environment, have been associated with granulomatous disease. This paper utilizes a previously described carbon nanoparticle granuloma model to address the issue of whether peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear transcription factor and negative regulator of inflammatory cytokines might play a role in granulomatous lung disease. PPARγ is constitutively expressed in alveolar macrophages from healthy individuals but is depressed in alveolar macrophages of patients with sarcoidosis, a prototypical granulomatous disease. Our previous study of macrophage-specific PPARγ KO mice had revealed an intrinsically inflammatory pulmonary environment with an elevated pro-inflammatory cytokines profile as compared to wild-type mice. Based on such observations we hypothesized that PPARγ expression would be repressed in alveolar macrophages from animals bearing granulomas induced by MWCNT instillation.
Wild-type C57Bl/6 and macrophage-specific PPARγ KO mice received oropharyngeal instillations of multiwall carbon nanotubes (MWCNT) (100 μg). Bronchoalveolar lavage (BAL) cells, BAL fluids, and lung tissues were obtained 60 days post-instillation for analysis of granuloma histology and pro-inflammatory cytokines (osteopontin, CCL2, and interferon gamma [IFN-γ] mRNA and protein expression.
In wild-type mice, alveolar macrophage PPARγ expression and activity were significantly reduced in granuloma-bearing animals 60 days after MWCNT instillation. In macrophage-specific PPARγ KO mice, granuloma formation was more extensive than in wild-type at 60 days after MWCNT instillation. PPARγ KO mice also demonstrated elevated pro-inflammatory cytokine expression in lung tissue, laser-microdissected lung granulomas, and BAL cells/fluids, at 60 days post MWCNT exposure.
Overall, data indicate that PPARγ deficiency promotes inflammation and granuloma formation, suggesting that PPARγ functions as a negative regulator of chronic granulomatous inflammation.
Respiratory research 01/2013; 14(1):7. DOI:10.1186/1465-9921-14-7 · 3.09 Impact Factor
"This is particularly relevant since AM play a critical role in pathogenesis of asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis (IPF) and lung sarcoidosis (for review see ). Moreover PPARγ binding to the respective response elements in AMs is markedly reduced in chronic inflammatory pulmonary sarcoidosis and obstructive diseases [26,27]. This suggests that the alveolar microenvironment might be immuno-suppressive in the absence of a specific stimulus , keeping the AM in a quiescent mode possibly supported by PPARγ function. "
[Show abstract][Hide abstract] ABSTRACT: The alveolar macrophage (AM) - first line of innate immune defence against pathogens and environmental irritants - constitutively expresses peroxisome-proliferator activated receptor γ (PPARγ). PPARγ ligand-induced activation keeps the AM quiescent, and thereby contributes to combat invaders and resolve inflammation by augmenting the phagocytosis of apoptotic neutrophils and inhibiting an excessive expression of inflammatory genes. Because of these presumed anti-inflammatory functions of PPARγ we tested the hypothesis, whether reduced functional receptor availability in mutant mice resulted in increased cellular and molecular inflammatory response during acute inflammation and/or in an impairment of its resolution.
To address this hypothesis we examined the effects of a carbon-nanoparticle (CNP) lung challenge, as surrogate for non-infectious environmental irritants, in a murine model carrying a dominant-negative point mutation in the ligand-binding domain of PPARγ (P465L/wt). Animals were instilled intratracheally with Printex 90 CNPs and bronchoalveolar lavage (BAL) was gained 24 h or 72 h after instillation to investigate its cellular and protein composition.
Higher BAL cell numbers - due to higher macrophage counts - were found in mutants irrespective of treatment. Neutrophil numbers in contrast were slightly lower in mutants. Intratracheal CNP instillation resulted in a profound recruitment of inflammatory neutrophils into the alveolus, but genotype related differences at acute inflammation (24 h) and resolution (72 h) were not observed. There were no signs for increased alveolar-capillary membrane damage or necrotic cell death in mutants as determined by BAL protein and lactate-dehydrogenase content. Pro-inflammatory macrophage-derived cytokine osteopontin was higher, but galectin-3 lower in female mutants. CXCL5 and lipocalin-2 markers, attributed to epithelial cell stimulation did not differ.
Despite general genotype-related differences, we had to reject our hypothesis of an increased CNP induced lung inflammation and an impairment of its resolution in PPARγ defective mice. Although earlier studies showed ligand-induced activation of nuclear receptor PPARγ to promote resolution of lung inflammation, its reduced activity did not provide signs of resolution impairment in the settings investigated here.
[Show abstract][Hide abstract] ABSTRACT: The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes upon ligand binding. As endogenous ligands, oxidized fatty acids and prostanoids can bind to and activate the receptor. Natural and synthetic PPARgamma activators have been studied extensively in many inflammatory settings and in most instances they have been shown to be anti-inflammatory. In this review we give an overview of the different molecular mechanisms how PPARgamma and its agonists exert their anti-inflammatory effects both at the cellular level and the level of the organism. The action of PPARgamma in acute and chronic inflammatory diseases and disease models will be presented.
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