Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma}.
Neutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-gamma in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-gamma, which is up-regulated by the sepsis-induced cytokines TNF-alpha and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-gamma ligands troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-gamma construct. Inhibition of chemotaxis by PPAR-gamma ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-gamma was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-gamma antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-gamma activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, USA. rajuc@umich.edu
Raju C
RC
Reddy
Venkata R
VR
Narala
Venkateshwar G
VG
Keshamouni
Jami E
JE
Milam
Michael W
MW
Newstead
Theodore J
TJ
Standiford
D000199:Actins / Q000276:immunology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D002839:Chromans / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018805:Sepsis / Q000276:immunology*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
C457499:2-chloro-5-nitrobenzanilide; D000199:Actins; D000813:Anilides; D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; D002839:Chromans; C508598:IL4 protein, human; D016209:Interleukin-8; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009240:N-Formylmethionine Leucyl-Phenylalanine; C037112:9-deoxy-delta-9-prostaglandin D2; D005340:Fibrinogen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077288:Troglitazone; D015230:Prostaglandin D2