Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production.
We have recently reported the identification of four novel members of the interleukin-1 (IL-1) family which we designated as IL-1 homologue 1-4 (IL-1H1-4). These proteins exhibit significant sequence homology to other members of the IL-1 family. Of these homologues, only IL-1H4 (renamed IL-1F7b) was predicted to contain a propeptide domain and a caspase cleavage site. We now report that caspase-1 cleaves IL-1F7b at the predicted site to generate mature IL-1F7b. Caspase-4 was also able to process IL-1F7b, albeit inefficiently. Other caspases and Granzyme-B did not cleave IL-1F7b. Furthermore, adenovirus-mediated expression of IL-1F7b in HEK 293 cells led to in situ processing and secretion of mature IL-1F7b. In a screen to identify a potential receptor, both pro and mature IL-1F7b bound to the soluble IL-18 receptor alpha-Fc (IL-18Ralpha-Fc) but not to the soluble IL-1R-Fc or ST2R-Fc fusion proteins. Mature IL-1F7b bound to the IL-18Ralpha-Fc protein with higher affinity than the pro form, although the affinities for both proteins were significantly lower than that observed for IL-18. Consistent with this observation, only IL-18 and not IL-1F7b induced IFN-gamma production by KG1a cells. We also report that pro and mature IL-1F7b form homodimers with association constants of 4 microM and 5 nM, respectively, suggesting biological relevance to IL-1F7b processing. Finally, we have localized the expression of IL-1F7b protein in discrete cell populations including plasma cells and tumor cells. These data suggest that IL-1F7b may be involved in immune response, inflammatory diseases and/or cancer.
Kumar
Sanjay
S
Musculoskeletal Diseases, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA, 19406, USA. sanjay.kumar-1@gsk.com
Hanning
Charles R
CR
Brigham-Burke
Michael R
MR
Rieman
David J
DJ
Lehr
Ruth
R
Khandekar
Sanjay
S
Kirkpatrick
Robert B
RB
Scott
Gilbert F
GF
Lee
John C
JC
Lynch
Frank J
FJ
Gao
Wentao
W
Gambotto
Andrea
A
Lotze
Michael T
MT
D000595:Amino Acid Sequence; D001665:Binding Sites; D020170:Caspase 1 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin / Q000378:metabolism*; D053724:Receptors, Interleukin-18; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D018076:DNA, Complementary; C508572:IL18R1 protein, human; D007375:Interleukin-1; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D011993:Recombinant Fusion Proteins; C471352:interleukin-1 homolog 4, human; D007371:Interferon-gamma; D020169:Caspases; D020170:Caspase 1