Pertussis toxin (PTX) B subunit and the nontoxic PTX mutant PT9K/129G inhibit Tat-induced TGF-beta production by NK cells and TGF-beta-mediated NK cell apoptosis.
We show that the pertussis toxin B oligomer (PTX-B), and the PTX mutant PT9K/129G, which is safely administered in vivo, inhibit both transcription and secretion of TGF-beta elicited by HIV-1 Tat in NK cells. Tat-induced TGF-beta mRNA synthesis is also blocked by the ERK1 inhibitor PD98059, suggesting that ERK1 is needed for TGF-beta production. Moreover, Tat strongly activates the c-Jun component of the multimolecular complex AP-1, whereas TGF-beta triggers c-Fos and c-Jun. Of note, treatment of NK cells with PTX-B or PT9K/129G inhibits Tat- and TGF-beta-induced activation of AP-1. TGF-beta enhances starvation-induced NK cell apoptosis, significantly reduces transcription of the antiapoptotic protein Bcl-2, and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-beta-mediated effects are prevented by PTX-B or PT9K/129G through a PI3K-dependent mechanism, as demonstrated by use of the specific PI3K inhibitor, LY294002. Finally, PTX-B and PT9K/129G up-regulate Bcl-x(L), the isoform of Bcl-x that protects cells from starvation-induced apoptosis. It is of note that in NK cells from patients with early HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x(L) was consistently lower than that in healthy donors; interestingly, TGF-beta and Tat were detected in the sera of these patients. Together, these data suggest that Tat-induced TGF-beta production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.
Zocchi
M Raffaella
MR
Laboratory of Tumor Immunology and AIDS Immunopathogenesis Unit, Department of Immunology and Infectious Diseases, Scientific Institute San Raffaele, Milan, Italy.
Contini
Paola
P
Alfano
Massimo
M
Poggi
Alessandro
A
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D019943:Amino Acid Substitution / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000502:physiology*; D005998:Glycine / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008239:Lysine / Q000235:genetics; D037342:Pertussis Toxin / Q000235:genetics* / Q000276:immunology* / Q000633:toxicity; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology / Q000633:toxicity; D051020:bcl-X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus
D000276:Adjuvants, Immunologic; C494811:BCL2L1 protein, human; D015696:Gene Products, tat; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D022223:Vaccines, Subunit; D051020:bcl-X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; D037342:Pertussis Toxin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine; D005998:Glycine