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* Department of Genitourinary Medical Oncology,
Department of Cancer Biology, and
Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030; and
Department of Molecular Cell Function,
¶ Department of Cell Pathology, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
TWEAK (TNF-like weak inducer of apoptosis) is a TNF superfamily member implicated in several mechanisms. Although fibroblast growth factor inducible 14 (Fn14)/TweakR has been reported as its receptor, an as yet unrecognized surface molecule(s) might modulate TWEAK function(s). Thus, we set out to identify TWEAK-binding proteins by screening a combinatorial peptide library. Cyclic peptides containing a consensus motif (WXDDG) bound to TWEAK specifically. These peptides were similar to CD163, a scavenger receptor cysteine-rich domain family member, restricted to the monocyte/macrophage lineage and responsible for the uptake of circulating haptoglobin-hemoglobin (Hp-Hb) complexes. Sequence profile analysis suggested that TWEAK mimicked the CD163 natural ligand (Hp-Hb). Consistently, we show dose-dependent TWEAK binding to CD163 and blockade by an anti-CD163 Ab. In a competition assay, both soluble CD163 and Fn14/TweakR were able to compete off TWEAK binding to coated Fn14/TweakR or CD163, respectively. Flow-cytometry and immunofluorescence assays showed that human monocytes (Fn14/TweakR negative and CD163 positive) bind TWEAK, thus blocking the recognition of CD163 and reducing the activation mediated by a specific mAb in these cells. We demonstrate that monocytes can sequester TWEAK from supernatants, thus preventing tumor cell apoptosis; this effect was reverted by preincubation with the peptide mimicking CD163 or with a mAb anti-CD163, indicating specificity. Finally, we show that recombinant human TWEAK binding to CD163-transfected Chinese hamster ovary cells is inhibited by the presence of either unlabeled TWEAK or the Hp-Hb complex. Together, these data are consistent with the hypothesis that CD163 either acts as a TWEAK scavenger in pathological conditions or serves as an alternate receptor for TWEAK in cells lacking Fn14/TweakR.
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.
1 This work was supported by National Institutes of Health Grants CA90270 and CA82976 (to R.P.) and CA90270 and CA90810 (to W.A.) and by awards from the Gillson-Longenbaugh Foundation, the V Foundation, and AngelWorks (to R.P. and W.A.). M.C.-V. was supported by a postdoctoral fellowship from the Susan G. Komen Breast Cancer Foundation. R.R. is an Odyssey Scholar supported by the Odyssey Program and the H-E-B Award for Scientific Achievement at University of Texas M. D. Anderson Cancer Center.
2 L.C.B. and M.C.-V. contributed equally to this study.
3 Current address: Department of Immunology, University of Texas M. D. Anderson Cancer Center.
4 Address correspondence and reprint requests to Dr. Renata Pasqualini or Wadih Arap, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374, Houston, TX 77030. E-mail addresses: warap{at}mdanderson.org or rpasqual{at}mdanderson.org
5 Abbreviations used in this paper: SRCR, scavenger receptor cystein rich; CHO, Chinese hamster ovary; Cy3, cyanine 3; EGF, epidermal growth factor; Fn14, fibroblast growth factor inducible 14; Hb, hemoglobin; Hp, haptoglobin; rHuTWEAK, recombinant human TWEAK; 125I-rHuTWEAK, 125I-labeled rHuTWEAK; TU, transforming unit.
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