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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

2002; Elsevier BV; Volume: 18; Issue: 2 Linguagem: Inglês

10.1006/cyto.2002.0873

1096-0023

Sanjay Kumar, Charles R. Hanning, Michael Brigham‐Burke, David J. Rieman, Ruth Lehr, Sanjay Khandekar, Robert B. Kirkpatrick, Gilbert Scott, John C. Lee, Frank J. Lynch, Wentao Gao, Andrea Gambotto, Michael T. Lotze,

Immune Cell Function and Interaction

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.