Requirement of apoptosis-inducing kinase 1 for the induction of bronchial asthma following stimulation with ovalbumin.
BACKGROUND
Bronchial asthma is a chronic inflammatory disease of the airway. Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, is activated by environmental stress and plays a crucial role in the induction of apoptosis and inflammation. To examine whether ASK1 is involved in the induction of bronchial asthma, we investigated the role of ASK1 using a genetic approach in the production of cytokines, as well as the development of airway hyperreactivity (AHR) and antibody responses using a murine airway inflammation model.


METHODS
ASK1-deficient (ASK1(-/-)) and control wild-type (WT) mice were immunized with ovalbumin (OVA) without alum intraperitoneally, followed by intranasal administration of OVA. Airway infiltration of inflammatory cells, cytokine production, AHR and antibody production were assayed. The asthmatic phenotype was assessed following intranasal administration of IL-13 or TNF-α.


RESULTS
ASK1(-/-) mice sensitized with OVA displayed an impaired inflammatory cell infiltration into airways and a decreased AHR relative to WT mice. Moreover, the production of OVA-specific IgE antibodies and proasthmatic cytokines (IL-5, IL-13 and TNF-α) was substantially reduced in OVA-stimulated ASK1(-/-) mice. Intranasal administration of IL-13 and OVA enhanced the accumulation of inflammatory cells in OVA-primed ASK1(-/-) mice. The OVA-induced AHR in response to methacholine was enhanced by IL-13 in WT mice but not ASK1(-/-) mice.


CONCLUSIONS
The ASK1 signaling pathway regulates the OVA-induced asthmatic phenotype, specifically AHR sensitivity and cytokine production. Therefore, the ASK1 signaling pathway is a promising target for therapeutic intervention in some asthmatic patients.
Department of Immunology, Tokyo Medical University, Tokyo, Japan.
Eiko
E
Takada
Masae
M
Furuhata
Susumu
S
Nakae
Hidenori
H
Ichijo
Katsuko
K
Sudo
Junichiro
J
Mizuguchi
D000818:Animals; D017209:Apoptosis; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D020397:Goblet Cells / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation; D018793:Interleukin-13 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016210:Methacholine Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D010047:Ovalbumin; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism
D018793:Interleukin-13; D015848:Interleukin-5; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse