Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9).
Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated with coordinate gene induction. Using DNA microarray analysis, we have identified a large panel of AAI signature genes. Unexpectedly, the allergen-challenged lung (a T helper 2 microenvironment) was found to be associated with the expression of T helper 1-associated CXCR3 ligands, monokine induced by IFN-gamma (Mig), and IFN-gamma-inducible protein of 10 kDa (IP-10). Here we report that Mig functions as a negative regulator of murine eosinophils. Whereas Mig was not able to induce chemotaxis of eosinophils, pretreatment with Mig induced a dose-dependent inhibition of chemoattractant-induced eosinophil transmigration in vitro. Moreover, i.v. administration of low doses of Mig ( approximately 10-30 microg/kg) induced strong and specific dose-dependent inhibition of chemokine-, IL-13-, and allergen-induced eosinophil recruitment and, conversely, neutralization of Mig before allergen challenge increased airway eosinophilia. Importantly, Mig also inhibited a CCR3-mediated functional response in eosinophils. These results indicate that the ultimate distribution and function of inflammatory cells within the allergic lung is dictated by a balance between positively and negatively regulatory chemokines. The identification of a naturally occurring eosinophil inhibitory chemokine pathway in vivo provides a strategic basis for future therapeutic consideration.
Fulkerson
Patricia C
PC
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45257-0524, USA.
Zimmermann
Nives
N
Brandt
Eric B
EB
Muntel
Emily E
EE
Doepker
Matthew P
MP
Kavanaugh
Jessica L
JL
Mishra
Anil
A
Witte
David P
DP
Zhang
Hongwei
H
Farber
Joshua M
JM
Yang
Ming
M
Foster
Paul S
PS
Rothenberg
Marc E
ME
D000485:Allergens / Q000276:immunology; D000818:Animals; D054413:Chemokine CCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019743:Chemokines, CXC / Q000235:genetics / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008024:Ligands; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D000485:Allergens; C515456:CCL11 protein, human; C515350:CCR3 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D008024:Ligands; D012333:RNA, Messenger; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D010047:Ovalbumin