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Nicotinic receptor β2 determines NK cell-dependent metastasis in a murine model of metastatic lung cancer.

Hao J, Shi FD, Abdelwahab M, Shi SX, Simard A, Whiteaker P, Lukas R, Zhou Q - PLoS ONE (2013)

Bottom Line: Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2.This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine.Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. jhao0216@gmail.com

ABSTRACT
Cigarette smoke exposure markedly compromises the ability of the immune system to protect against invading pathogens and tumorigenesis. Nicotine is a psychoactive component of tobacco products that acts as does the natural neurotransmitter, acetylcholine, on nicotinic receptors (nAChRs). Here we demonstrate that natural killer (NK) cells strongly express nAChR β2. Nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2. This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine. Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.

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Nicotine alters NK cell phenotype via nAChR β2.Wild type (β2+/+) or nAChR β2 knock-out (β2−/−) mice received nicotine (Nic) or PBS for 21 days before they were scarified. Single cell suspensions were prepared from spleens. Frequency and phenotypes of NK cells within the mononuclear cells were analyzed by FACS. A. Expression of NKG2D, NKG2A and Ly49I on gated NK1.1+CD3− cells. B. Expression of perforin and granzyme B secreted by gated NK1.1+CD3− cells. The plot data represents results from two separate experiments (n = 3–4 mice/group). P values, Student’s t-test, *p<0.05.
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pone-0057495-g002: Nicotine alters NK cell phenotype via nAChR β2.Wild type (β2+/+) or nAChR β2 knock-out (β2−/−) mice received nicotine (Nic) or PBS for 21 days before they were scarified. Single cell suspensions were prepared from spleens. Frequency and phenotypes of NK cells within the mononuclear cells were analyzed by FACS. A. Expression of NKG2D, NKG2A and Ly49I on gated NK1.1+CD3− cells. B. Expression of perforin and granzyme B secreted by gated NK1.1+CD3− cells. The plot data represents results from two separate experiments (n = 3–4 mice/group). P values, Student’s t-test, *p<0.05.

Mentions: NK cell functions are dictated by stimulatory and inhibitory receptors on NK cells. Activating signals are generated through NK group 2 member (NKG2D), which recognize the stress-inducible molecules MHC class I chain-related proteins (MICA and MICB) and the UL-16-binding proteins 1-4 (ULBP1-4), also known as RAET proteins, or through natural cytotoxicity receptors (NCRs) that recognize viral hemagglutinin and as yet undefined tumor-associated ligand. The inhibitory signals are generated by binding of MHC class I molecules to killer cell immunoglobulin-like receptors (KIRs) in humans, or to Ly49 in mice, in addition to the CD94/NKG2A heterodimer in both species [22], [23]. We compared the expression of several of these receptors on spleen NK cells isolated from nicotine- or PBS- exposed mice and investigated the influence, if any, of nAChR β2 deficiency. Expression of inhibitory receptor NKG2A is not significantly altered on NK cells by nicotine; whereas expression of NKG2D and Ly49I were reduced in mice that received nicotine, and such reductions are largely abrogated in nAChR β2−/− mice (Figure 2A) [13]. Similar findings were obtained regarding expression of NK cell effector molecular Granzyme B and perforin (Figure 2B). We also observed that nicotine has a similar effect on lung-derived NK cells receptor profile and effector molecules (data not shown).


Nicotinic receptor β2 determines NK cell-dependent metastasis in a murine model of metastatic lung cancer.

Hao J, Shi FD, Abdelwahab M, Shi SX, Simard A, Whiteaker P, Lukas R, Zhou Q - PLoS ONE (2013)

Nicotine alters NK cell phenotype via nAChR β2.Wild type (β2+/+) or nAChR β2 knock-out (β2−/−) mice received nicotine (Nic) or PBS for 21 days before they were scarified. Single cell suspensions were prepared from spleens. Frequency and phenotypes of NK cells within the mononuclear cells were analyzed by FACS. A. Expression of NKG2D, NKG2A and Ly49I on gated NK1.1+CD3− cells. B. Expression of perforin and granzyme B secreted by gated NK1.1+CD3− cells. The plot data represents results from two separate experiments (n = 3–4 mice/group). P values, Student’s t-test, *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585320&req=5

pone-0057495-g002: Nicotine alters NK cell phenotype via nAChR β2.Wild type (β2+/+) or nAChR β2 knock-out (β2−/−) mice received nicotine (Nic) or PBS for 21 days before they were scarified. Single cell suspensions were prepared from spleens. Frequency and phenotypes of NK cells within the mononuclear cells were analyzed by FACS. A. Expression of NKG2D, NKG2A and Ly49I on gated NK1.1+CD3− cells. B. Expression of perforin and granzyme B secreted by gated NK1.1+CD3− cells. The plot data represents results from two separate experiments (n = 3–4 mice/group). P values, Student’s t-test, *p<0.05.
Mentions: NK cell functions are dictated by stimulatory and inhibitory receptors on NK cells. Activating signals are generated through NK group 2 member (NKG2D), which recognize the stress-inducible molecules MHC class I chain-related proteins (MICA and MICB) and the UL-16-binding proteins 1-4 (ULBP1-4), also known as RAET proteins, or through natural cytotoxicity receptors (NCRs) that recognize viral hemagglutinin and as yet undefined tumor-associated ligand. The inhibitory signals are generated by binding of MHC class I molecules to killer cell immunoglobulin-like receptors (KIRs) in humans, or to Ly49 in mice, in addition to the CD94/NKG2A heterodimer in both species [22], [23]. We compared the expression of several of these receptors on spleen NK cells isolated from nicotine- or PBS- exposed mice and investigated the influence, if any, of nAChR β2 deficiency. Expression of inhibitory receptor NKG2A is not significantly altered on NK cells by nicotine; whereas expression of NKG2D and Ly49I were reduced in mice that received nicotine, and such reductions are largely abrogated in nAChR β2−/− mice (Figure 2A) [13]. Similar findings were obtained regarding expression of NK cell effector molecular Granzyme B and perforin (Figure 2B). We also observed that nicotine has a similar effect on lung-derived NK cells receptor profile and effector molecules (data not shown).

Bottom Line: Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2.This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine.Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. jhao0216@gmail.com

ABSTRACT
Cigarette smoke exposure markedly compromises the ability of the immune system to protect against invading pathogens and tumorigenesis. Nicotine is a psychoactive component of tobacco products that acts as does the natural neurotransmitter, acetylcholine, on nicotinic receptors (nAChRs). Here we demonstrate that natural killer (NK) cells strongly express nAChR β2. Nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2. This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine. Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.

Show MeSH
Related in: MedlinePlus