title: IL-4 promotes asymmetric dimethylarginine accumulation, oxo-nitrative stress, and hypoxic response-induced mitochondrial loss in airway epithelial cells.
abstract: Obesity is known to increase asthma risk and severity. Increased levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with mitochondrial toxicity, asthma, and metabolic syndrome. IL-4 upregulates the expression of protein arginine methyltransferases, which are essential for ADMA formation. Importantly, cross-talk between IL-4, ADMA, and mitochondrial dysfunction could explain how obesity and IL-4 can synergize to exacerbate allergic inflammation.
  
  
  
  We sought to investigate how IL-4, a key asthma-associated cytokine, can influence ADMA-related effects on lungs.
  
  
  
  BEAS2B (bronchial epithelial) cells were treated with IL-4 followed by ADMA and investigated for oxo-nitrative stress and resultant mitochondrial toxicity after 48 hours by using flow cytometry, confocal imaging, immunoblotting, and fluorimetric assays.
  
  
  
  IL-4-induced mitotoxicity in BEAS2B cells was significantly higher in the presence of exogenous ADMA. IL-4 treatment led to proteolytic degradation of dimethylarginine dimethylaminohydrolase 2, which catabolizes ADMA. IL-4 pretreatment was associated with increased intracellular ADMA accumulation and increased ADMA-induced mitotoxicity. Airway epithelial cells treated with IL-4 followed by ADMA showed exaggerated oxo-nitrative stress and potent induction of the cellular hypoxic response, despite normoxic conditions. The hypoxic response was associated with reduced mitochondrial function but was reversible by overexpression of the mitochondrial biogenesis factor, mitochondrial transcription factor A.
  
  
  
  We conclude that IL-4 promotes intracellular ADMA accumulation, leading to mitochondrial loss through oxo-nitrative stress and hypoxic response. This provides a novel understanding of how obesity, with high ADMA levels, and asthma, with high IL-4 levels, might potentiate each other and highlights the potential of mitochondrial-targeted therapeutics in obese subjects with asthma.
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Bijay
authors.initials: B
authors.lastname: Pattnaik
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Bodas
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Naveen Kumar
authors.initials: NK
authors.lastname: Bhatraju
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Pant
authors.affiliation: Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Delhi, India.
authors.forename: Randeep
authors.initials: R
authors.lastname: Guleria
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Balaram
authors.initials: B
authors.lastname: Ghosh
authors.affiliation: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India. Electronic address: a.agrawal@igib.in.
authors.forename: Anurag
authors.initials: A
authors.lastname: Agrawal
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D017209:Apoptosis; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001249:Asthma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D015847:Interleukin-4; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D002154:Calpain; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: ADMA; IL-4; hypoxic response; mitochondria; mitochondrial transcription factor A