Abstract
Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease and alters expression of proteolytic enzymes that contribute to disease pathology. Previously, we reported that smoke exposure leads to the induction of matrix metalloproteinase-1 (MMP-1) through the activation of ERK1/2, which is critical to the development of emphysema. To date, the upstream signaling pathway by which cigarette smoke induces MMP-1 expression has been undefined. This study demonstrates that cigarette smoke mediates MMP-1 expression via activation of the TLR4 signaling cascade. In vitro cell culture studies demonstrated that cigarette smoke-induced MMP-1 was regulated by TLR4 via MyD88/IRAK1. Blockade of TLR4 or inhibition of IRAK1 prevented cigarette smoke induction of MMP-1. Mice exposed to acute levels of cigarette smoke exhibited increased TLR4 expression. To further confirm the in vivo relevance of this signaling pathway, rabbits exposed to acute cigarette smoke were found to have elevated TLR4 signaling and subsequent MMP-1 expression. Additionally, lungs from smokers exhibited elevated TLR4 and MMP-1 levels. Therefore, our data indicate that TLR4 signaling, through MyD88 and IRAK1, plays a predominant role in MMP-1 induction by cigarette smoke. The identification of the TLR4 pathway as a regulator of smoke-induced protease production presents a series of novel targets for future therapy in chronic obstructive pulmonary disease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cells, Cultured
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Female
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Gene Expression Regulation, Enzymologic / drug effects*
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Gene Expression Regulation, Enzymologic / genetics
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Humans
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Interleukin-1 Receptor-Associated Kinases / genetics
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Male
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Matrix Metalloproteinase 1 / biosynthesis*
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Matrix Metalloproteinase 13 / biosynthesis*
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Mice
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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Pulmonary Disease, Chronic Obstructive / genetics
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Pulmonary Disease, Chronic Obstructive / metabolism*
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Pulmonary Disease, Chronic Obstructive / pathology
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Pulmonary Disease, Chronic Obstructive / therapy
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Rabbits
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Tobacco Smoke Pollution / adverse effects*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism*
Substances
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MYD88 protein, human
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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TLR4 protein, human
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Tlr4 protein, mouse
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Tobacco Smoke Pollution
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Toll-Like Receptor 4
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IRAK1 protein, human
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Interleukin-1 Receptor-Associated Kinases
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Irak1 protein, mouse
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse
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MMP1 protein, human
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Matrix Metalloproteinase 1