HIF-1 expression is associated with CCL2 chemokine expression in airway inflammatory cells: implications in allergic airway inflammation
1 Hospital Infantil de Mexico, Federico Gomez, Unidad de Investigacion en Enfermedades Oncologicas, Dr. Marquez No 262, Col. Doctores, Delegacion Cuahutemos, Mexico City, Mexico CP. 06720
2 Facultad de Medicina Programa de Postgrado; Doctorado en Ciencias Biomedicas UNAM, Mexico City, Mexico
3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
4 ChemRisk, LLC, Aliso Viejo, CA, USA
5 Department of Clinical Immunology and Allergy, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
6 Experimental Pathology Section, Department of Pathology, National Institute of Medical Science and Nutrition, Salvador Zubiran, Mexico City, Mexico
7 Unidad de Investigacion Medica en Enfermedades Oncologicas, CMN SXXI, IMSS, Mexico City, Mexico
8 Departamento de Inmunología, Instituto de Investigaciones Biomédicas, UNAM, México, Mexico
9 Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
10 Department of Microbiology Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA
11 Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Respiratory Research 2012, 13:60 doi:10.1186/1465-9921-13-60Published: 23 July 2012
The pathogenesis of allergic airway inflammation in asthmatic patients is complex and characterized by cellular infiltrates and activity of many cytokines and chemokines. Both the transcription factor hypoxia inducible factor-1 (HIF-1) and chemokine CCL2 have been shown to play pivotal roles in allergic airway inflammation. The interrelationship between these two factors is not known. We hypothesized that the expression of HIF-1 and CCL2 may be correlated and that the expression of CCL2 may be under the regulation of HIF-1. Several lines of evidence are presented to support this hypothesis.
The effects of treating wild-type OVA (ovalbumin)-sensitized/challenged mice with ethyl-3,4-dihydroxybenzoate (EDHB), which upregulate HIF, on CCL2 expression, were determined. Mice conditionally knocked out for HIF-1β was examined for their ability to mount an allergic inflammatory response and CCL2 expression in the lung after intratracheal exposure to ovalbumin. The association of HIF-1α and CCL2 levels was also measured in endobronchial biopsies and bronchial fluid of asthma patients after challenge.
We show that both HIF-1α and CCL2 were upregulated during an OVA (ovalbumin)-induced allergic response in mice. The levels of HIF-1α and CCL2 were significantly increased following treatment with a pharmacological agent which upregulates HIF-1α, ethyl-3,4-dihydroxybenzoate (EDHB). In contrast, the expression levels of HIF-1α and CCL2 were decreased in the lungs of mice that have been conditionally knocked out for ARNT (HIF-1β) following sensitization with OVA when compared to levels in wild type mice. In asthma patients, the levels of HIF-1α and CCL2 increased after challenge with the allergen.
These data suggest that CCL2 expression is regulated, in part, by HIF-1 in the lung. These findings also demonstrate that both CCL2 and HIF-1 are implicated in the pathogenesis of allergic airway inflammation.