IL-4 promotes asymmetric dimethylarginine accumulation, oxo-nitrative stress, and hypoxic response-induced mitochondrial loss in airway epithelial cells

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• 作者：Bijay Pattnaik ; MSc^a ; Manish Bodas ; PhD^a ; Naveen Kumar Bhatraju ; PhD^a ; Tanveer Ahmad ; PhD^a ; Richa Pant ; MSc^a ; Randeep Guleria ; MD ; DM^b ; Balaram Ghosh ; PhD^a ; Anurag Agrawal ; MD ; PhD^a ; ^{a.agrawal@igib.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IL-4 ; ADMA ; hypoxic response ; mitochondrial transcription factor A ; mitochondria
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：138
• 期：1
• 页码：130-141.e9
• 全文大小：3565 K

文摘

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.

Objective

We sought to investigate how IL-4, a key asthma-associated cytokine, can influence ADMA-related effects on lungs.

Methods

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.

Results

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.

Conclusion

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.