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(American Journal of Pathology. 2005;166:1217-1228.)
© 2005 American Society for Investigative Pathology

Analysis of Interleukin-27 (EBI3/p28) Expression in Epstein-Barr Virus- and Human T-Cell Leukemia Virus Type 1-Associated Lymphomas

Heterogeneous Expression of EBI3 Subunit by Tumoral Cells

Frédérique Larousserie^*,, Emilie Bardel^*, Stefan Pflanz, Bertrand Arnulf, Carmen Lome-Maldonado^¶, Olivier Hermine^*, Laurence Brégeaud, Monique Perennec, Nicole Brousse, Rob Kastelein and Odile Devergne^*

From the CNRS UMR 8147,^* Université Paris V, Institut Fédératif de Recherche Necker, Paris, France; Unité Propre de Recherche de l’Enseignement Supérieur EA 219, Service d’Anatomie Pathologique, Assistance Publique–Hôpitaux de Paris, Hôpital Necker, Paris, France; the Service d’Immuno-Hématologie, Hôpital St. Louis, Paris, France; DNAX Research Institute, Palo Alto, California; and the Department of Pathology,^¶ Instituto Nacional de Ciencias Medicas Y Nutricion Salvador Zubiran, Mexico City, Mexico

Interleukin (IL)-27 is a novel heterodimeric cytokine of the IL-12 family that is composed of two subunits, Epstein-Barr virus (EBV)-induced gene 3 (EBI3) and p28. EBI3 is expressed at high levels in EBV-transformed B-cell lines and is induced in vitro by the EBV oncogene LMP1 in a nuclear factor (NF)-B-dependent manner. We show here that EBI3 expression is up-regulated in human T-cell leukemia virus type 1 (HTLV-1)-infected cell lines and IL-2-dependent leukemic cells from adult T-cell leukemia/lymphoma (ATL) patients, compared to normal activated T cells. EBI3 expression was decreased in HTLV-1-transformed cells after treatment with the NF-B inhibitor BAY11-7082 and was induced in Jurkat cells by expression of HTLV-1 wild-type Tax oncoprotein, but not by the Tax mutant M22, which is defective for NF-B activation. In situ analysis of EBI3 and p28 expression in Hodgkin’s lymphomas (HLs), in various EBV-associated lymphoproliferative disorders (LPDs) (including post-transplant LPDs and nasal-type NK/T-cell lymphomas), and in ATL showed that EBI3 was expressed by neoplastic cells in all cases of HL and of LMP1-positive EBV-associated LPD, at variable levels in ATL cases, but rarely in control T-cell lymphomas. In contrast, in all lymphomas tested, no or few tumoral cells expressed p28. Consistent with these data, no significant p28 or IL-27 expression was detected in HL-derived cell lines, or in EBV- or HTLV-1-transformed cell lines. This selective overexpression of EBI3 by transformed cells suggests that EBI3 may play a role, independently from its association to p28, in regulating anti-viral or anti-tumoral immune responses.

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