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Blood, 1 November 2006, Vol. 108, No. 9, pp. 2906-2913. Prepublished online as a Blood First Edition Paper on July 18, 2006; DOI 10.1182/blood-2006-05-024638.
CHEMOKINES, CYTOKINES, AND INTERLEUKINS Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylationFrom the Departments of Immunology and Biochemistry, Surgery and Anatomy, and Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto; Department of Pharmacology, Institute of Biology, Universidade do Estado do Rio de Janeiro; and Department of Biological Sciences, Federal University of Triângulo Mineiro, Uberaba, Brazil.
The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients with sepsis (52) and 15 volunteers were prospectively enrolled. Patients presented increased circulating levels of tumor necrosis factor-
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
, interferon-
, interleukin (IL)–8, and IL-10. Patients showed reduced neutrophil chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4) or IL-8. No difference in the transcription or expression of the IL-8 receptor, CXCR1, was detected in neutrophils from controls and patients. However, septic neutrophils failed to increase tyrosine phosphorylation and actin polymerization in response to IL-8 or LTB4. In contrast, septic neutrophils, similar to controls, showed phagocytic activity that induced actin polymerization and augmented phosphotyrosine content. Treatment of control neutrophils with cytokines and lipopolysaccharide (LPS) to mimic endogenous septic environment inhibited actin polymerization and tyrosine phosphorylation in response to IL-8 or LTB4. High expression of G protein–coupled receptor kinase 2 (GRK2) and GRK5 was detected in septic neutrophils and control cells treated with cytokines plus LPS. Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants. 
