title: Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism.
abstract: The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-kappaB motif in its proximal promoter, whereas IL-9 receptor-alpha (IL-9Ralpha) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Ralpha in ATL, a neutralizing monoclonal antibody directed toward IL-9Ralpha inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Ralpha on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Ralpha/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Mike
authors.initials: M
authors.lastname: Petrus
authors.forename: Bonita R
authors.initials: BR
authors.lastname: Bryant
authors.forename: Vinh
authors.initials: V
authors.lastname: Phuc Nguyen
authors.forename: Mindy
authors.initials: M
authors.lastname: Stamer
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Goldman
authors.forename: Richard
authors.initials: R
authors.lastname: Bamford
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: John E
authors.initials: JE
authors.lastname: Janik
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016356:Gene Products, tax / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D016906:Interleukin-9 / Q000235:genetics* / Q000502:physiology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology* / Q000473:pathology; D009000:Monocytes; D019899:Paracrine Communication; D053651:Receptors, Interleukin-9 / Q000502:physiology*; D013601:T-Lymphocytes
chemical_list: D016356:Gene Products, tax; D016906:Interleukin-9; D053651:Receptors, Interleukin-9