Regulation of ITAM-positive receptors: role of IL-12 and IL-18.
Our previous studies have identified mechanisms by which cytokine production, blocked by Ly49G2 receptor cross-linking, can be overridden. In this study we analyzed the regulation of other ITAM-positive receptor signaling on NK, NKT, and T cells and characterized the biochemical pathways involved in this signaling. Our studies demonstrate that cross-linking of NKG2D and NK1.1 results in a synergistic NK IFN-gamma response when combined with IL-12 or IL-18. Examination of NKT- and T-cell responses demonstrated that cross-linking of NKG2D and CD3 resulted in potent synergy when combined with IL-12 and, to a lesser degree, with IL-18. We have now found that both the p38 MAP kinase and the ERK-dependent signal transduction pathways are required for the synergistic response. Further mechanistic examination of the synergy indicated a potent up-regulation of total IFN-gamma mRNA in the nuclear and the cytoplasmic compartment, but mRNA half-life was not affected. Fifteen minutes of IL-12 pretreatment was sufficient to result in maximal synergistic activation, indicating that the response of the cells to the IL-12 signal was rapid and immediate. Thus, our data demonstrate that multiple convergent signals maximize the innate immune response by triggering complementary biochemical signaling pathways.
Ortaldo
John R
JR
Laboratory of Experimental Immunology and Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research, Frederick, MD 21702-1201, USA.
Winkler-Pickett
Robin
R
Wigginton
Jon
J
Horner
Meagan
M
Bere
Earl W
EW
Mason
Anna T
AT
Bhat
Narayan
N
Cherry
James
J
Sanford
Michael
M
Hodge
Deborah L
DL
Young
Howard A
HA
D019943:Amino Acid Substitution; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D012260:Ribonucleases; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000950:Antigens, Ly; D016207:Cytokines; D020382:Interleukin-18; C527086:Klrk1 protein, mouse; D037181:Lectins, C-Type; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D018664:Interleukin-12; D007371:Interferon-gamma; D012260:Ribonucleases