Abstract
Both NK cells and IL-15 play crucial roles in innate immunity against viral infections and cancer. Cigarette smoke is known to increase susceptibility to infections and certain cancers. Interleukin (IL)-15 plays an important role in immune responses by regulating proliferation, survival and functions of NK cells. Here, we examined the impact of cigarette smoke on IL-15 production and IL-15 mediated NK cell functions in human PBMCs. We report that cigarette smoke significantly suppresses the induction of IL-15 by poly I:C in human PBMCs. Serum IL-15 levels among smokers was significantly lower than non-smokers. In contrast to a profound increases in intracellular IL-15/IL-15Ralpha in poly I:C-treated PBMCs, exposure of PBMCs to smoke-conditioned media (SCM) diminished the IL-15/IL-15Ralpha production. We examined if inhibition of IL-15 production could lead to less NK cell activation. Interestingly, SCM-treated PBMCs had diminished up-regulation of NK cell activation marker, CD69, but not NKG2D compared with controls after poly I:C stimulation. We then confirmed by using IL-15 neutralizing antibody as well as exogenous IL-15 that the ploy I:C-induced NK cells activation was IL-15 mediated. More importantly, cigarette smoke significantly impaired NK cell cytolytic potential to kill K562 cancer cells which was found to be IL-15 mediated. The inhibition of IL-15 and its regulatory NK cell activities were linked to attenuated STAT3 and STAT5, but not ERK1/2 phosphorylations. We demonstrate, for the first time, that cigarette smoke compromises IL-15 production and as a result NK cell function which could link to the higher incidence of cancers or viral infections observed among smokers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / drug effects
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / drug effects
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism
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Culture Media, Conditioned / pharmacology
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Cytotoxicity, Immunologic / drug effects
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Cytotoxicity, Immunologic / immunology
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Extracellular Signal-Regulated MAP Kinases / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Interferon Inducers / pharmacology
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Interleukin-15 / antagonists & inhibitors*
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Interleukin-15 / blood
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Interleukin-15 Receptor alpha Subunit / antagonists & inhibitors
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Interleukin-15 Receptor alpha Subunit / immunology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Lectins, C-Type
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology*
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NK Cell Lectin-Like Receptor Subfamily K / drug effects
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NK Cell Lectin-Like Receptor Subfamily K / immunology
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NK Cell Lectin-Like Receptor Subfamily K / metabolism
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Nicotiana / adverse effects*
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Phosphorylation / drug effects
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Phosphorylation / immunology
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Poly I-C / pharmacology
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / antagonists & inhibitors
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STAT5 Transcription Factor / immunology
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STAT5 Transcription Factor / metabolism
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Smoke / adverse effects*
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Smoking / adverse effects*
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Smoking / blood
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Smoking / immunology
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Culture Media, Conditioned
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Interferon Inducers
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Interleukin-15
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Interleukin-15 Receptor alpha Subunit
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KLRK1 protein, human
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Lectins, C-Type
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NK Cell Lectin-Like Receptor Subfamily K
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Smoke
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Extracellular Signal-Regulated MAP Kinases
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Poly I-C