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TLR3 Ligand Induces NF-B Activation and Various Fates of Multiple Myeloma Cells Depending on IFN- Production¹

David Chiron^*,, Catherine Pellat-Deceunynck^*,, Martine Amiot^*,, Régis Bataille^*, and Gaëtan Jego^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 892, Nantes, France; and Université de Nantes, Unité Mixte de Recherche-S892, Nantes, France

Multiple myeloma (MM) cells express TLR. It has been shown that TLR ligands induce the proliferation, survival, and immune surveillance escape of MM cells through MyD88-TLR pathways. Deciphering TLR function in MM cells will help in understanding the mechanisms of tumor cell growth. In this study, we examined the response of MM cells to the MyD88-independent/TIR-domain-containing adapter-inducing IFN-β-dependent TLR3. Deregulation of NF-B pathway is a feature of MM cells, and we wondered whether TLR3 activation could mobilize the NF-B pathway. We show that five of seven human myeloma cell line (HMCL) cells expressed TLR3. In the presence of the synthetic TLR3 ligand (poly(I:C)), activation of NF-B pathway was observed in three of five selected TLR3⁺ HMCL, NCI-H929, RPMI 8226, and KMM1. In agreement with NF-B activation, only these three HMCL responded to poly(I:C), although by either an increase (KMM1) or a decrease (NCI-H929, RPMI 8226) of proliferation. We show that KMM1 increase of proliferation was prevented by NF-B inhibitor. In contrast, inhibition of proliferation in both NCI-H929 and RPMI 8226 was due to IFN--induced apoptosis. We next demonstrated that p38 MAPK pathway controlled both IFN- secretion and IFN--mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway. In conclusion, our results show that TLR3 ligand induces NF-B pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.

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 grants from La ligue Contre le Cancer (to G.J.; Equipe labellisée 2008).

² Address correspondence and reprint requests to Dr. Gaëtan Jego, Institut National de la Santé et de la Recherche Médicale, Unité 892, 9 quai Moncousu, 44093 Nantes, France. E-mail address: gaetanjego{at}yahoo.fr

³ Abbreviations used in this paper: DC, dendritic cell; HMCL, human myeloma cell line; MM, multiple myeloma; TRAF, TNFR-associated factor; TRIF, TIR-domain-containing adapter-inducing IFN-β; pDC, plasmacytoid DC.

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