Ratio of local to systemic chemokine concentrations regulates neutrophil recruitment

Am J Pathol. 2001 Feb;158(2):715-21. doi: 10.1016/S0002-9440(10)64014-X.

Abstract

CXC chemokines are important regulators of local neutrophil recruitment. In this study, we examined the role of the ratio of local to systemic chemokine concentrations as a significant factor determining local neutrophil recruitment. Thioglycollate was injected intraperitoneally into BALB/c mice resulting in a dose-dependent increase in neutrophil recruitment and local inflammation, as measured by peritoneal levels of interleukin 6. At the high dose of 3% thioglycollate, antibody inhibition of the murine chemokines KC and macrophage inflammatory protein-2 caused a reduction in peritoneal neutrophil recruitment by as much as 93%. A paradoxical effect was observed with a 0.3% thioglycollate intraperitoneal challenge. In this situation, inhibition of KC resulted in a significant increase in peritoneal neutrophils, and inhibition of macrophage inflammatory protein-2 also resulted in increased peritoneal neutrophils. These results were consistent with a reverse chemotactic gradient as described by the ratio of peritoneal to plasma KC levels. A higher ratio (ie, increased peritoneal chemokines compared to plasma) resulted in increased neutrophil recruitment after either the 3% or 0.3% thioglycollate challenge. Our results demonstrate that whereas sufficient local concentrations of chemokines are necessary, a critical factor dictating local neutrophil recruitment is the ratio of the local to the systemic chemokine concentrations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Chemokine CXCL2
  • Chemokines / blood
  • Chemokines / immunology
  • Chemokines / metabolism*
  • Dose-Response Relationship, Drug
  • Injections, Intraperitoneal
  • Interleukin-6 / blood
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Monokines / immunology
  • Neutrophils / cytology*
  • Neutrophils / drug effects
  • Peritoneum / cytology
  • Peritoneum / drug effects
  • Peritoneum / metabolism
  • Thioglycolates / pharmacology

Substances

  • Antibodies, Monoclonal
  • Chemokine CXCL2
  • Chemokines
  • Interleukin-6
  • Monokines
  • Thioglycolates