Beta(3)-mediated engulfment of apoptotic tumor cells by dendritic cells is dependent on CAMKII: inhibition by HIV-1 Tat.
In this paper, we show that the engulfment of apoptotic tumor cells by DC requires the activation of the calcium-calmodulin kinase II (CAMKII). Indeed, DC phagocytosis of apoptotic lymphoma cells is consistently inhibited by KN62 and KN93, two blockers of CAMKII, but not by the inactive compound KN92. Wortmannin and LY294002, two inhibitors of the phosphatidyl-inositol-3 kinase, slightly decrease the phagocytosis of apoptotic cells, at variance with PD98059, an inhibitor of the mitogen-activated protein kinase. It is interesting that the addition of synthetic HIV-1 Tat, which we demonstrated to inhibit phagocytosis and calcium influx in DC, blocks the activation of CAMKII elicited via beta(3) integrin, which is involved in apoptotic body engulfment by DC. Experiments performed with Tat-derived peptides showed that this inhibition is mediated by the C-terminal domain of Tat. Finally, pertussis toxin can prevent HIV-1 Tat-mediated inhibition, suggesting the involvement of a guanosine triphosphate-binding (G) protein in DC-mediated phagocytosis.
Poggi
Alessandro
A
Laboratory of Immunology, Unit of Protein Biology, National Cancer Research Institute, Genoa, Italy.
Carosio
Roberta
R
Rubartelli
Anna
A
Zocchi
Maria Raffaella
MR
D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003713:Dendritic Cells / Q000473:pathology / Q000502:physiology*; D004789:Enzyme Activation; D015696:Gene Products, tat / Q000494:pharmacology / Q000502:physiology*; D015497:HIV-1; D006801:Humans; D039661:Integrin beta3; D009369:Neoplasms / Q000473:pathology*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D015696:Gene Products, tat; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases