Exposure to cigarette smoke suppresses IL-15 generation and its regulatory NK cell functions in poly I:C-augmented human PBMCs.
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.
Mian
M Firoz
MF
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Pek
Elizabeth A
EA
Mossman
Karen L
KL
Stämpfli
Martin R
MR
Ashkar
Ali A
AA
D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000097:blood; D053720:Interleukin-15 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects* / Q000097:blood / Q000276:immunology; D014026:Nicotiana / Q000009:adverse effects*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017077:Culture Media, Conditioned; D048049:Extracellular Signal-Regulated MAP Kinases; D007369:Interferon Inducers; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D037181:Lectins, C-Type; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011070:Poly I-C; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012906:Smoke; D000099192:CD69 Antigens; C527085:KLRK1 protein, human; C494086:STAT3 protein, human