Abstract
KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IκB kinase β (IKKβ) and the phosphorylation and degradation of IκBα, which indicate activation of the classical NF-κB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-α, IFN-γ, MIP1α, MIP1β, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-γ, IL-8, and MIP1α production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-κB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcεRI-γ association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-κB pathway and selectively stimulated the production of MIP1α, but not that of IFN-γ or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcεRI-γ; and 2) through another receptor domain independent of the transmembrane arginine.
Original language | English |
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Pages (from-to) | 2922-2932 |
Number of pages | 11 |
Journal | Journal of Immunology |
Volume | 180 |
Issue number | 5 |
DOIs | |
State | Published - Mar 1 2008 |
Keywords
- Amino Acid Sequence
- Amino Acid Substitution/genetics
- Animals
- Arginine/genetics
- Cell Line, Tumor
- Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
- Humans
- Killer Cells, Natural/enzymology
- MAP Kinase Signaling System/genetics
- Mice
- Mice, Inbred DBA
- Molecular Sequence Data
- NF-kappa B/metabolism
- Protein Structure, Tertiary/genetics
- Receptors, IgE/genetics
- Receptors, KIR2DL4/chemistry
- Signal Transduction/genetics