Genomic analysis of chemokine and chemokine receptor expression in experimental allergic asthma

Abstract

1 7 Genomic Analysis of Chemokine and Chemokine Receptor l / Expression in Experimental Allergic Asthma Patricia C Fulkerson, Nives Zimmermann, Elizabeth A Moulton, Bruce J Aronow, ME Rothenberg Children's Hospital of Cincinnati, Cincinnati, OH Chemokines are a family of small secreted proteins involved in the pathogenesis of inflammatory disease by contributing to the recruitment and activation of specific cell populations. A variety of chemokines have been demonstrated to be strongly induced in models of allergic inflammation. Traditional studies have been limited to determining the role of one, or at most a few, chemokine(s) and chemokine receptor(s) in allergic inflammation. However, DNA microarray techniques allow researchers to study how multiple genes contribute to the pathogenesis of complex diseases. We used an Affymetrix DNA oligonucleotide microarray to screen cDNA derived from total lung RNA of mice challenged with ovalbumin or saline in order to identify gene expression profiles altered by allergic inflammation. Of the 12,423 genes analyzed, only 2.7% of the genes were reproducibly increased, indicating a limited subset of genes induced during experimental asthma. Among the induced genes, there was a striking bias for chemokine and chemokine receptor genes. Of the 47 chemokine related genes on the microarray, we identified 14 (30%) chemokine and chemokine receptor genes that had significant induction following allergen challenge compared with controls (CCL2, CCL6, CCL7, CCL8, CCL9, CCL11, CCLI2, CXCL9, CXCL10, CXCL12, CCR1, CCR2, CCR3 and CCR5). We confirmed the results obtained on the DNA microarray by Northern blot analysis. Surprisingly, a majority of the induced chemokines were clustered on specific loci on mouse chromosome 11 at 47cM and on chromosome 5 at 53cM. The receptors were all from the same locus on mouse chromosome 9 at 72cM. Chemokines on other loci on chromosomes 1, 4, 5 and 8 were not significantly affected by allergen challenge. This data suggests that allergic airway inflammation is mediated in part by regulation of specific locus control regions on mouse chromosomes 9, 5 and 11, and highlights the value of DNA microarray technology in the analysis of allergic responses.