Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice.
BACKGROUND
There is growing evidence that hypoxia-inducible transcription factors are involved in the pathophysiology of asthma. Hypoxia-inducible factor-1alpha (HIF-1alpha) in particular controls the expression of many hypoxia regulated genes, but whether HIF-1alpha directly contributes to allergen-driven immune responses is not known.


METHODS
Partially HIF-1alpha-deficient mice (HIF-1alpha(+/-)) or wild-type littermate controls were used in all experiments. Spleen CD4+ T cells were stimulated with anti-CD3 plus anti-CD28 antibodies and cytokine secretion was measured in vitro. Mice were sensitized by intraperitoneal injection of ovalbumin (Ova) plus alum, and then challenged by intranasal Ova followed by bronchoalveolar lavage (BAL) and isolation of spleen cells. BAL cells were counted and the differential determined using cytospin, and splenocytes were incubated with Ova to measure recall cytokine production.


RESULTS
Interferon-gamma secretion was significantly higher in anti-CD3 plus anti-CD28 stimulated CD4+ T cells obtained from HIF-1alpha(+/-) mice compared to wild-type controls. HIF-1alpha(+/-) mice were protected from lung eosinophilia 72 h after allergen challenge, in association with enhanced secretion of interferon-gamma in recall responses of splenocytes.


CONCLUSIONS
HIF-1alpha contributes to allergic immune responses and lung eosinophilia in a mouse model of asthma.
Guo
Jia
J
Division of Pulmonary and Critical Care, University of Rochester Medical Center, Rochester 14642, NY, USA.
Lu
Wenju
W
Shimoda
Larissa A
LA
Semenza
Gregg L
GL
Georas
Steve N
SN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin