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The Journal of Immunology, 2002, 169: 6467-6473.
Copyright © 2002 by The American Association of Immunologists

Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation

Eva García-Ramallo*, Teresa Marques*, Neus Prats*, Jordi Beleta*, Steven L. Kunkel{dagger} and Nuria Godessart1,*

* Department of Pharmacology, Almirall Prodesfarma Research Center, Barcelona, Spain; and {dagger} Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109

The mechanistic relationships between initiating stimulus, cellular source and sequence of chemokine expression, and leukocyte recruitment during inflammation are not clear. To study these relationships in an acute inflammatory process, we challenged a murine air pouch with carrageenan. A time-dependent increase in TNF-{alpha}, monocyte chemottractant protein-1 (MCP-1), macrophage-inflammatory protein-1{alpha} (MIP-1{alpha}), RANTES, KC, and MIP-2 was found in the exudates preceding cell recruitment, but displaying different kinetic profiles. Air pouches generated for 2, 6, or 9 days before initiating inflammation demonstrated a proportional increase in the number of cells lining the cavities. Two hours after carrageenan stimulation, the synthesis of TNF-{alpha} and all chemokines but RANTES increased in proportion to the lining cellularity, although no differences in infiltrating leukocytes were found, suggesting that the early source of these mediators is resident cells. To assess the contribution of neutrophils to chemokine synthesis at later time points, we used neutropenic animals. Neutrophil depletion caused a decrease in TNF-{alpha} (51%), KC (37%), MIP-1{alpha} (30%), and RANTES (57%) levels and a 2-fold increase in monocytes 4 h after challenge. No effect on MIP-2 and MCP-1 levels was observed. The selective blockade of CXCR2 or CCR1 inhibited neutrophil recruitment by 74% and 54%, respectively, without a significant inhibition of monocytes. A differential effect on TNF-{alpha} and MCP-1 levels was observed after these treatments, indicating that the two receptors did not subserve a mere redundant chemotactic role. Overall, our results suggest that chemokines synthesized by resident cells play an important role in the evolution of the inflammatory response.




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