Peroxisome proliferator-activated receptor-gamma agonists modulate macrophage activation by gram-negative and gram-positive bacterial stimuli.
Bacterial products, such as lipopolysaccharide (LPS) or heat-killed Escherichia coli (EC), and heat-killed Staphylococcus aureus (SA) are potent activators of macrophages (MØ). When stimulated by these bacterial components, MØ produce inflammatory mediators, such as nitric oxide (NO) and thromboxane (Tx) B(2). Bacterial mediator production is preceded by the activation of various signal transduction pathways. Agonists that activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been shown to block MØ mediator production by LPS and other stimuli. However, very little is known about the effects of PPARgamma agonists on SA- or EC-induced MØ activation. Therefore, we investigated whether the PPARgamma agonists 15-deoxy-Delta12,14 prostaglandin J(2) (15-PGJ(2)) and troglitazone block LPS-, EC-, or SA-induced mediator production. Rat peritoneal MØ were stimulated with LPS, EC, or SA (10 microg/mL) with or without increasing concentrations (0.1 to 10 microM) of each PPARgamma agonist and NO and TxB(2) production were measured. 15-PGJ(2) decreased LPS-, EC-, and SA-induced NO and TxB(2) production. However, troglitazone only inhibited the production of TxB(2) by each stimuli. In parallel studies, the effects of PPARgamma agonists on signaling pathways were evaluated. Rat peritoneal MØ were pretreated for 1 h with 15-PGJ(2) or troglitazone (1 or 10 microM) and then stimulated for 40 min with LPS, EC, or SA (10 microg/mL). Western blot analysis demonstrated that 15-PGJ(2) significantly inhibited LPS-, EC-, and SA-induced ERK (1/2) activation and blocked IkappaBalpha degradation. Troglitazone had no significant effect on either signaling protein. The data demonstrate that although both 15-PGJ(2) and troglitazone are considered PPARgamma agonists, they differentially affect mediator production and cell signaling events. PPARgamma-independent effects of 15-PGJ(2) may contribute to its more potent anti-inflammatory effects compared with troglitazone.
Guyton
Kelly
K
Department of Microbiology, Medical University of South Carolina, 167 Ashley Avenue, Charleston, SC 29425, USA.
Zingarelli
Basilia
B
Ashton
Sarah
S
Teti
Giuseppi
G
Tempel
George
G
Reilly
Chris
C
Gilkeson
Gary
G
Halushka
Perry
P
Cook
James
J
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000472:pathogenicity; D006090:Gram-Negative Bacteria / Q000276:immunology; D006094:Gram-Positive Bacteria / Q000276:immunology; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013211:Staphylococcus aureus / Q000472:pathogenicity; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013929:Thromboxane B2 / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D009569:Nitric Oxide; D013929:Thromboxane B2; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2