p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells.
Natural killer (NK) cells are a component of the innate immunity against viral infections through their rapid cytotoxic activity and cytokine production. Although the synthetic double-stranded (ds) RNA polyinosinic-polycytidylic acid (poly I:C), a mimic of a common product of viral infections, is known to rapidly up-regulate their in vivo functions, NK cell ability to directly respond to dsRNA is still mostly unknown. Our results show that treatment with poly I:C significantly up-regulates both natural and CD16-mediated cytotoxicity of highly purified human NK cells. Poly I:C also induces the novel capability of producing CXCL10 chemokine in human NK cells and synergistically enhances interferon-gamma (IFN-gamma) production induced by either adaptive or innate cytokines. In accordance with the expression of Toll-like receptor-3 (TLR3) and of TRIF/TICAM-1 adaptor, poly I:C stimulation induces the activation of interferon regulatory factor-3 (IRF-3) transcription factor and of p38 mitogen-activated protein kinase (MAPK) in human NK cells. Finally, we demonstrate that p38 MAPK activity is required for the dsRNA-dependent enhancement of cytotoxicity and CXCL10 production. The occurrence of dsRNA-induced signaling and functional events closely correlates with the TLR3 mRNAprofile in different NK cell populations. Taken together, these data identify p38 as a central component of NK cell ability to directly respond to dsRNA pathogen-associated molecular pattern (PAMP).
Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena, 324, 00161 Rome, Italy.
Simona
S
Pisegna
Gianluca
G
Pirozzi
Mario
M
Piccoli
Luigi
L
Frati
Angela
A
Santoni
Gabriella
G
Palmieri
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics*; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D017931:DNA Primers; D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D011956:Receptors, Cell Surface; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C