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.
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.
Chen
Jing
J
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Petrus
Mike
M
Bryant
Bonita R
BR
Phuc Nguyen
Vinh
V
Stamer
Mindy
M
Goldman
Carolyn K
CK
Bamford
Richard
R
Morris
John C
JC
Janik
John E
JE
Waldmann
Thomas A
TA
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
D016356:Gene Products, tax; D016906:Interleukin-9; D053651:Receptors, Interleukin-9