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This version published online on May 15, 2003
Endocrinology, doi:10.1210/en.2002-0144
A more recent version of this article appeared on August 1, 2003
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Submitted on December 16, 2002
Accepted on May 5, 2003

Functional characterisation of W147A: A high affinity interleukin-11 antagonist

Nicholas Underhill-Day1*, Lisa A. McGovern1, Natalia Karpovich1, Helen J Mardon1, Victoria A. Barton1, and John K. Heath1

1 Cancer Research UK Growth Factor Group. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT. United Kingdom. ôPresent Address, Geneflow Limited, Fradley Business Park, Wood End Lane, Fradley, Staffordshire, WS13 8NF; Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU; Present Address, KuDOS Pharmaceuticals, 327 Cambridge Science Park, Milton Road, Cambridge. CB4 OWG

* To whom correspondence should be addressed. E-mail: N.UnderhillDay{at}bham.ac.uk.

Interleukin-11 (IL-11) is a member of the gp130 family of cytokines, which signal via assembly of multi-subunit receptor complexes containing at least one molecule of the transmembrane signaling receptor gp130. IL-11 forms a high affinity complex, thereby inducing gp130-dependent signaling. Previous studies have identified three distinct receptor binding sites, I, II and III, crucial for the binding of murine IL-11 (mIL-11) to both the IL-11R and gp130. In this study, we have further characterized the role of the mIL-11 site III mutant W147A. We show that W147A is a high affinity specific antagonist of mIL-11-mediated signaling in gp130/IL-11R-transfected Ba/F3 cells. The antagonistic action of W147A is due to its ability to competitively disrupt multimeric gp130/IL-11R signaling complex formation. We also show that W147A inhibits IL-11-mediated signaling in primary human endometrial cells thus demonstrating the potential utility of W147A in suppressing IL-11 responses in vivo.
Key words: interleukin • endometrial • STAT






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