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 Blood, 15 November 2008, Vol. 112, No. 10, pp. 4250-4258.
Prepublished online as a Blood First Edition Paper on June 5, 2008; DOI 10.1182/blood-2007-12-128967.

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PHAGOCYTES

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma}

Raju C. Reddy1, Venkata R. Narala1, Venkateshwar G. Keshamouni1, Jami E. Milam1, Michael W. Newstead1, and Theodore J. Standiford1

1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor

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 J2 (15d-PGJ2) 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.


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