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J. Biol. Chem., Vol. 279, Issue 14, 13677-13688, April 2, 2004

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Interleukin (IL)-1F6, IL-1F8, and IL-1F9 Signal through IL-1Rrp2 and IL-1RAcP to Activate the Pathway Leading to NF-B and MAPKs^*

Jennifer E. Towne, Kirsten E. Garka, Blair R. Renshaw, G. Duke Virca, and John E. Sims

From the Amgen Corporation, Seattle, Washington 98101

Interleukin 1 (IL-1) plays a prominent role in immune and inflammatory reactions. Our understanding of the IL-1 family has recently expanded to include six novel members named IL-1F5 to IL-1F10. Recently, it was reported that IL-1F9 activated NF-B through the orphan receptor IL-1 receptor (IL-1R)-related protein 2 (IL-1Rrp2) in Jurkat cells (Debets, R., Timans, J. C., Homey, B., Zurawski, S., Sana, T. R., Lo, S., Wagner, J., Edwards, G., Clifford, T., Menon, S., Bazan, J. F., and Kastelein, R. A. (2001) J. Immunol. 167, 1440–1446). In this study, we demonstrate that IL-1F6 and IL-1F8, in addition to IL-1F9, activate the pathway leading to NF-B in an IL-1Rrp2-dependent manner in Jurkat cells as well as in multiple other human and mouse cell lines. Activation of the pathway leading to NF-B by IL-1F6 and IL-1F8 follows a similar time course to activation by IL-1, suggesting that signaling by the novel family members occurs through a direct mechanism. In a mammary epithelial cell line, NCI/ADR-RES, which naturally expresses IL-1Rrp2, all three cytokines signal without further receptor transfection. IL-1Rrp2 antibodies block activation of the pathway leading to NF-B by IL-1F6, IL-1F8, and IL-1F9 in both Jurkat and NCI/ADR-RES cells. In NCI/ADR-RES cells, the three IL-1 homologs activated the MAPKs, JNK and ERK1/2, and activated downstream targets as well, including an IL-8 promoter reporter and the secretion of IL-6. We also provide evidence that IL-1RAcP, in addition to IL-1Rrp2, is required for signaling by all three cytokines. Antibodies directed against IL-1RAcP and transfection of cytoplasmically deleted IL-1RAcP both blocked activation of the pathway leading to NF-B by the three cytokines. We conclude that IL-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP.

Received for publication, January 6, 2004 , and in revised form, January 18, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Amgen Corp., 51 University St., Seattle, WA 98101. Tel.: 206-265-5062; Fax: 206-624-7496; E-mail: townej{at}amgen.com.

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