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-γ PRODUCTION

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2002-04, Vol.18 (2), p.61-71
• Main Authors: Kumar, Sanjay, Hanning, Charles R., Brigham-Burke, Michael R., Rieman, David J., Lehr, Ruth, Khandekar, Sanjay, Kirkpatrick, Robert B., Scott, Gilbert F., Lee, John C., Lynch, Frank J., Gao, Wentao, Gambotto, Andrea, Lotze, Michael T.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Caspase 1 - metabolism; Caspases - metabolism; Cell Line; DNA, Complementary; Humans; Interferon-gamma - biosynthesis; Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-18 - metabolism; Interleukin-18 Receptor alpha Subunit; interleukin/homologues/caspase 1/processing/inflammation; Receptors, Interleukin - metabolism; Receptors, Interleukin-18; Recombinant Fusion Proteins - metabolism
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1006/cyto.2002.0873

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 α-Fc (IL-18Rα-Fc) but not to the soluble IL-1R-Fc or ST2R-Fc fusion proteins. Mature IL-1F7b bound to the IL-18Rα-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-γ production by KG1a cells. We also report that pro and mature IL-1F7b form homodimers with association constants of 4μM and 5nM, 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.