Abstract
Introduction
Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS).
Methods
Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small-interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay.
Results
CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells.
Conclusions
These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.
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References
Ford ES, Mannino DM, Zhao G et al (2012) Changes in mortality among United States adults with chronic obstructive pulmonary disease in two national cohorts recruited during 1971 through 1975 and 1988 through. Chest 141:101–110
Lopez AD, Murray CC et al (1998) The global burden of disease, 1990–2020. Nat Med 4:1241–1243
Rabe KF, Hurd S, Anzueto A et al (2007) Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:523–555
Barnes PJ (2000) Chronic obstructive pulmonary disease. N Engl J Med 343:269–280
Coppé JP, Desprez PY et al (2010) The senescence associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118
Hara H, Araya J et al (2012) Involvement of creatine kinase B in cigarette smoke-induced bronchial epithelial cell senescence. Am J Respir Cell Mol Biol 46:306–312
Fujii S, Hara H, Araya J, et al (2012) Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology 1:630–641
Kroemer G, Marinõ G et al (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293
Ogata M, Hino S, Saito A et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231
Chaachouay H, Ohneseit P, Toulany M et al (2011) Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother Oncol 99:287–292
Kim HP, Wang X, Chen ZH et al (2008) Autophagic proteins regulate cigarette smoke-induced apoptosis: protective role of heme oxygenase-1. Autophagy 4:887–895
Chen ZH, Kim HP, Sciurba FC et al (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE 3:e3316
Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
Nabeshima Y (2002) Klotho: a fundamental regulator of aging. Ageing Res Rev 1:627–638
Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833
Koh N, Fujimori T, Nishiguchi S et al (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020
Kamitani A, Yamada H, Kinuta M et al (2002) Distribution of dynamins in testis and their possible relation to spermatogenesis. Biochem Biophys Res Commun 294:261–267
Miyamoto K, Ito M, Segawa H et al (2003) Molecular targets of hyperphosphataemia in chronic renal failure. Nephrol Dial Transplant 18(Suppl 3):iii79–iii80
Yamamoto M, Clark JD, Pastor JV et al (2005) Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 280:38029–38034
Rakugi H, Matsukawa N, Ishikawa K et al (2007) Antioxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 31:82–87
Li L, Wang Y, Gao W et al (2015) Klotho reduction in alveolar macrophages contributes to cigarette smoke extract-induced inflammation in chronic obstructive pulmonary disease. J Biol Chem 290:27890–27900
Carp H, Janoff A (1978) Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis 118:617–621
Kode A, Yang SR, Rahman I (2006) Differential effects of cigarette smoke on oxidative stress and proinflammatory cytokine release in primary human airway epithelial cells and in a variety of transformed alveolar epithelial cells. Respir Res 7:132–152
Moodie FM, Marwick JA, Anderson CS et al (2004) Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-ƙB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J 18:1897–1899
Yang SR, Chida AS, Bauter MR et al (2006) Cigarette smoke induces proinflammatory cytokine release by activation of NF-ƙB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol 291:L46–L57
Chen ZH, Lam HC, ** Y et al (2010) Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA 107:18880–18885
Hwang JW, Chung S et al (2010) Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 500:203–209
Mizushima N, Komatsu M et al (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741
Shimizu S, Kanaseki T et al (2004) Role of Bcl-2 family proteins in a nonapoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6:1221–1228
Choi AM, Ryter SW et al (2013) Autophagy in human health and disease. N Engl J Med 368:651–662
Lu L, Katsaros D, Wiley A et al (2008) Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression. Cancer Investig 26:185–192
Wolf I, Levanon-Cohen S, Bose S et al (2008) Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27:7094–70105
Abramovitz L, Rubinek T, Ligumsky H et al (2011) KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin Cancer Res 17:4254–4266
Kooijman R (2006) Regulation of apoptosis by insulin-like growth factor (IGF)-I. Cytokine Growth Factor Rev 17:305–323
Choi JE, Lee SS et al (2009) Insulin-like growth factor-I receptor blockade improves outcome in mouse model of lung injury. Am J Respir Crit Care Med 179:212–219
Chand HS, Woldegiorgis Z, Schwalm K et al (2012) Acute inflammation induces insulin-like growth factor-1 to mediate Bcl-2 and Muc5ac expression in airway epithelial cells. Am J Respir Cell Mol Biol 47:784–791
Kythreotis P, Kokkini A et al (2009) Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med 9:11
Pilewski JM, Liu L, Henry AC et al (2005) Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition. Am J Pathol 166:399–407
Lum JJ, Bauer DE, Kong M et al (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120:237–248
Arico S, Petiot A, Bauvy C et al (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276:35243–35246
Degtyarev M, De Mazière A, Orr C et al (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183:101–116
Mammucari C, Milan G, Romanello V et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471
Nyunoya T, Monick MM, Klingelhutz A et al (2006) Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35:681–688
Salminen A, Kaarniranta K (2009) Regulation of the aging process by autophagy. Trends Mol Med 15:217–224
Karrasch S, Holz O, Jorres RA (2008) Aging and induced senescence as factors in the pathogenesis of lung emphysema. Respir Med 102:1215–1230
Acknowledgements
We thank Yujie Wang for technical assistance and **n Yao for helpful discussion and assistance.
Funding
This study was funded by the Introduction of Talent (YR201107) and the Natural Science Program of Anhui Universities (No. KJ2017A274) .
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This article does not contain any studies with human participants or animals performed by any of the authors.
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Informed consent was obtained from all individual participants included in the study.
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Lingling Li, Min Zhang and Liqin Zhang have contributed equally to this work.
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Li, L., Zhang, M., Zhang, L. et al. Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD. Lung 195, 295–301 (2017). https://doi.org/10.1007/s00408-017-9997-1
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DOI: https://doi.org/10.1007/s00408-017-9997-1