Role of protein kinase C in TBT-induced inhibition of lytic function and MAPK activation in human natural killer cells.
Human natural killer (NK) cells are lymphocytes that destroy tumor and virally infected cells. Previous studies have shown that exposure of NK cells to tributyltin (TBT) greatly diminishes their ability to destroy tumor cells (lytic function) while activating mitogen-activated protein kinases (MAPK) (p44/42, p38, and JNK) in NK cells. The signaling pathway that regulates NK lytic function appears to include activation of protein kinase C(PKC) as well as MAPK activity. TBT-induced activation of MAPKs would trigger a portion of the NK lytic signaling pathway, which would then leave the NK cell unable to trigger this pathway in response to a subsequent encounter with a target cell. In the present study we evaluated the involvement of PKC in inhibition of NK lysis of tumor cells and activation of MAPKs caused by TBT exposure. TBT caused a 2–3-fold activation of PKC at concentrations ranging from 50 to 300 nM (16–98 ng/ml),indicating that activation of PKC occurs in response to TBT exposure. This would then leave the NK cell unable to respond to targets. Treatment with the PKC inhibitor, bisindolylmaleimide I, caused an 85% decrease in the ability of NK cells to lyse tumor cells, validating the involvement of PKC in the lytic signaling pathway. The role of PKC in the activation of MAPKs by TBT was also investigated using bisindolylmaleimide I. The results indicated that, in NK cells where PKC activation was blocked, there was no activation of the MAPK, p44/42 in response to TBT.However, TBT-induced activation of the MAPKs, p38 and JNK did not require PKC activation. These results indicate the pivotal role of PKC in the TBT-induced loss of NK lytic function including activation of p44/42 by TBT in NK cells.
Abraha
Abraham B
AB
Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
Rana
Krupa
K
Whalen
Margaret M
MM
D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000633:toxicity*
D014220:Trialkyltin Compounds; C011559:tributyltin; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases
Arch Toxicol. 2007 Apr;81(4):271-7
17019560
Cell Biol Toxicol. 2010 Oct;26(5):435-44
20213532
J Appl Toxicol. 2007 Jan-Feb;27(1):86-94
17149696
N Engl J Med. 1989 Jun 29;320(26):1731-5
2543925
Environ Pollut. 1995;90(3):279-90
15091461
Oncogene. 1997 Dec 11;15(24):2921-7
9416835
Cell Immunol. 1989 Feb;118(2):470-81
2910505
Circulation. 2005 Sep 27;112(13):1971-8
16172266
Biochem Biophys Res Commun. 2004 Mar 19;315(4):991-7
14985110
Science. 2004 Nov 26;306(5701):1517-9
15567854
Immunology. 1993 Aug;79(4):542-7
8406578
Environ Res. 1999 Aug;81(2):108-16
10433842
J Immunol. 1988 Nov 1;141(9):3164-9
3262683
Arch Dermatol. 1989 Oct;125(10):1406-12
2679403
J Immunol. 2001 Jun 15;166(12):7219-28
11390470
FASEB J. 1995 Apr;9(7):484-96
7737456
J Biol Chem. 1996 Feb 9;271(6):2886-91
8621675
Endocr Rev. 2001 Apr;22(2):153-83
11294822
Environ Res. 1987 Dec;44(2):335-53
3319574
J Immunol. 1986 Sep 15;137(6):1977-84
2427588
Int Immunol. 2004 Mar;16(3):385-93
14978012
Nat Immunol. 2000 Nov;1(5):419-25
11062502
Immunology. 2003 Jul;109(3):432-9
12807490
Environ Health Perspect. 1976 Apr;14:51-6
789069
J Biol Chem. 1992 Nov 25;267(33):23957-62
1429733
Cell Res. 2005 Jan;15(1):19-23
15686621
J Biol Chem. 1991 Aug 25;266(24):15771-81
1874734
Scand J Immunol. 2002 Mar;55(3):229-32
11940228
Cell Immunol. 1988 Apr 1;112(2):402-13
2833358
Trends Immunol. 2001 Nov;22(11):633-40
11698225
J Appl Toxicol. 2009 Mar;29(2):165-73
18989867
Nat Immunol. 2000 Nov;1(5):372-4
11062493
Toxicology. 2005 May 5;209(3):263-77
15795062
Nat Rev Mol Cell Biol. 2010 Feb;11(2):103-12
20094051
J Toxicol Environ Health A. 2001 Jun 22;63(4):273-87
11437060
Toxicol Appl Pharmacol. 1996 Jun;138(2):268-74
8658528
J Immunol. 2000 Aug 15;165(4):1782-9
10925255
J Exp Med. 1992 Dec 1;176(6):1751-5
1281218
J Immunol. 2000 Oct 1;165(7):3811-9
11034387
Toxicology. 2006 Jul 25;224(3):229-37
16781040
J Pediatr. 1982 May;100(5):727-30
6279813
Environ Res. 2002 Mar;88(3):199-209
12051798
J Toxicol Environ Health A. 1998 Nov 13;55(5):373-84
9829560
Bull Environ Contam Toxicol. 1995 Oct;55(4):510-6
8555674
Science. 1995 Feb 3;267(5198):682-5
7839144
J Immunol. 1998 Dec 15;161(12):6648-56
9862693
Adv Cancer Res. 2003;90:127-56
14710949
Environ Res. 2002 Jan;88(1):19-29
11896664
Nature. 1988 Aug 25;334(6184):661-5
3045562