The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines.
The IL-1 family member 7b (IL-1F7b) is a novel homolog of the IL-1 cytokine family discovered by computational cloning. We have reported that IL-1F7b shares critical amino acid residues with IL-18 and binds the IL-18-binding protein; in doing so, IL-1F7b augments the inhibition of IFN-gamma by the IL-18-binding protein. IL-1F7b also binds IL-18Ralpha but neither induces signal nor acts as a receptor antagonist. Hence, the function of IL-1F7b remains unknown. In the present study, we analyzed the intracellular expression pattern of IL-1F7b. Using two variants of GFP fusion constructs of human IL-1F7b stably expressed in RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor-but not the N-terminal propiece-specifically translocates to the nucleus following LPS stimulation. IL-1F7b, like IL-1beta, IL-18, and IL-33, is processed by caspase-1 to generate the mature cytokines. Therefore, we tested whether caspase-1-mediated cleavage of the IL-1F7b precursor is required for mature IL-1F7b to translocate actively into the nucleus. Indeed, a specific caspase-1 inhibitor markedly reduced nuclear entry of IL-1F7b. In stable transfectants of human IL-1F7b in RAW macrophages stimulated with LPS, levels of TNF-alpha, IL-1alpha, IL-6, as well as the chemokine MIP-2, were substantially reduced (72-98%) compared with LPS-stimulated cells transfected with the empty plasmid. These results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines, consistent with IL-1F7b being an anti-inflammatory member of the IL-1 family.
Sharma
Sheetal
S
Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
Kulk
Nicole
N
Nold
Marcel F
MF
Gräf
Ralph
R
Kim
Soo-Hyun
SH
Reinhardt
Dietrich
D
Dinarello
Charles A
CA
Bufler
Philip
P
D021581:Active Transport, Cell Nucleus; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; C471352:interleukin-1 homolog 4, human; D007371:Interferon-gamma; D020170:Caspase 1