Pertussis Toxin (PTX) B Subunit and the Nontoxic PTX Mutant PT9K/129G Inhibit Tat-Induced TGF-β Production by NK Cells and TGF-β-Mediated NK Cell Apoptosis

Abstract

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-β elicited by HIV-1 Tat in NK cells. Tat-induced TGF-β mRNA synthesis is also blocked by the ERK1 inhibitor PD98059, suggesting that ERK1 is needed for TGF-β production. Moreover, Tat strongly activates the c-Jun component of the multimolecular complex AP-1, whereas TGF-β triggers c-Fos and c-Jun. Of note, treatment of NK cells with PTX-B or PT9K/129G inhibits Tat- and TGF-β-induced activation of AP-1. TGF-β 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-β-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-xL, 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-xL was consistently lower than that in healthy donors; interestingly, TGF-β and Tat were detected in the sera of these patients. Together, these data suggest that Tat-induced TGF-β production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

Pertussis Toxin B-Oligomer Suppresses IL-6 Induced HIV-1 and Chemokine Expression in Chronically Infected U1 Cells via Inhibition of Activator Protein 1

“…These results support the hypothesis that PTX-B or related molecules, such as the genetically modified PT-9K/129G (83), which retains all the HIV inhibitory features of PTX-B (9,26,84), could represent potent new pharmacological agents against HIV infection, as we have also recently demonstrated in infected lymphoid histocultures (85) and hu-PBL SCID mice infected with HIV (86).…”

Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis

“…Regulatory feedback at IRIS onset may be exerted either by regulatory T cells or by subsets of NK cells secreting anti-inflammatory cytokines such as IL-10 and TGF-␤. 29,30 IL10-producing NK cells could suppress specific T-cell responses, 31 thereby controlling exaggerated responses during TB-IRIS. 23 IL10 and TGF-␤ are also able to down-regulate NK cell-activating receptors.…”

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

“…Tat has been shown to interact with some G-coupled protein receptors. as chemokine receptors (57), and several reports have shown that some of the activities of extracellular Tat including neurotoxic ones in astrocytes are blocked by PTx (58,59). The characterization of the putative Tat receptor deserves further studies.…”