TY - JOUR
T1 - Constitutive expression of IL-12R22 on human multiple myeloma cells delineates a novel therapeutic target
AU - Airoldi, Irma
AU - Cocco, Claudia
AU - Giuliani, Nicola
AU - Ferrarini, Marina
AU - Colla, Simona
AU - Ognio, Emanuela
AU - Taverniti, Giuseppe
AU - Di Carlo, Emma
AU - Cutrona, Giovanna
AU - Perfetti, Vittorio
AU - Rizzoli, Vittorio
AU - Ribatti, Domenico
AU - Pistoia, Vito
PY - 2008/8/1
Y1 - 2008/8/1
N2 - The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12Rβ2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12Rβ2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12Rβ2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCIH929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-γ, IFN-α, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-γ-related antiangiogenic pathway. Thus, IL-12Rβ2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.
AB - The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12Rβ2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12Rβ2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12Rβ2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCIH929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-γ, IFN-α, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-γ-related antiangiogenic pathway. Thus, IL-12Rβ2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.
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U2 - 10.1182/blood-2008-02-139378
DO - 10.1182/blood-2008-02-139378
M3 - Article
C2 - 18474725
AN - SCOPUS:50949131990
SN - 0006-4971
VL - 112
SP - 750
EP - 759
JO - Blood
JF - Blood
IS - 3
ER -