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Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-? activation in human monocytes.

ABSTRACT: OBJECTIVE:Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-? (PPAR?)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPAR?-stimulating activity. METHODS:Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50?ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPAR? activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPAR? gene silencing. RESULTS:In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-?B activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-?, inhibitor of ?B-?, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPAR? target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPAR? antagonism and PPAR? gene silencing. Anti-inflammatory effects of ARBs correlated with their PPAR? agonist potency. CONCLUSION:Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPAR? activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.

SUBMITTER: Pang T

PROVIDER: S-EPMC3237779 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes.

Pang Tao T Benicky Julius J Wang Juan J Orecna Martina M Sanchez-Lemus Enrique E Saavedra Juan M JM

Journal of hypertension 20120101 1

<h4>Objective</h4>Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-stimulating activity.<h4>Methods</h4>Human circulating monocytes and mo ...[more]

PMID: 22124178

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Project description:Although glucocorticoids (GC) represent the most frequently used immunosuppressive drugs, their effects are still not well understood. In our previous studies, we have shown that treatment of monocytes with GC does not cause a global suppression of monocytic effector functions, but rather induces differentiation of a specific anti-inflammatory phenotype. The anti-inflammatory role of peroxisome proliferator-activated receptor (PPAR)-? has been extensively studied during recent years. However, a relationship between GC treatment and PPAR-? expression in macrophages has not been investigated so far. Studies using PPAR-?-deficient mice have frequently provided controversial results. A potential reason is the use of primary cells, which commonly represent inhomogeneous populations burdened with side effects and influenced by bystander cells. To overcome this constraint, we established ER-Hoxb8-immortalized bone marrow-derived macrophages from Ppargfl/fl and LysM-Cre Ppargfl/fl mice in this study. In contrast to primary macrophages, the ER-Hoxb8 system allows the generation of a homogeneous and well-defined population of resting macrophages. We could show that the loss of PPAR-? resulted in delayed kinetic of differentiation of monocytes into macrophages as assessed by reduced F4/80, but increased Ly6C expression in early phases of differentiation. As expected, PPAR-?-deficient macrophages displayed an increased pro-inflammatory phenotype upon long-term LPS stimulation characterized by an elevated production of pro-inflammatory cytokines TNF-?, IL1-?, IL-6, IL-12 and a reduced production of anti-inflammatory cytokine IL-10 compared to PPAR-? WT cells. Moreover, PPAR-?-deficient macrophages showed impaired phagocytosis. GC treatment of macrophages led to the upregulation of PPAR-? expression. However, there were no differences in GC-induced suppression of cytokines between both cell types, implicating a PPAR-?-independent mechanism. Intriguingly, GC treatment resulted in an increased in vitro migration only in PPAR-?-deficient macrophages. Performing a newly developed in vivo cell-tracking experiment, we could confirm that GC induces an increased recruitment of PPAR-? KO, but not PPAR-? WT macrophages to the site of inflammation. Our findings suggest a specific effect of PPAR-? on GC-induced migration in macrophages. In conclusion, we could demonstrate that PPAR-? exerts anti-inflammatory activities and shapes macrophage functions. Moreover, we identified a molecular link between GC and PPAR-? and could show for the first time that PPAR-? modulates GC-induced migration in macrophages.

Dataset Information

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-? activation in human monocytes.

Publications

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes.

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