Soluble interleukin-13Ralpha2 decoy receptor inhibits Hodgkin's lymphoma growth in vitro and in vivo.
Recent studies have demonstrated that the malignant Reed-Sternberg cells of Hodgkin's lymphoma (HL) secrete and are responsive to interleukin (IL)-13. We hypothesized that overexpression of a soluble IL-13 decoy receptor (sIL-13Ralpha2) via adenoviral-mediated gene transfer would inhibit IL-13-induced Reed-Sternberg cell proliferation. Western blot and ELISA analysis verified expression of sIL-13Ralpha2 in cell lysates and supernatants of AdsIL-13Ralpha2-transduced COS-7 cells. Treatment of two IL-13-responsive HL-derived cell lines, HDLM-2 and L-1236, with AdsIL-13Ralpha2-conditioned medium, resulted in the inhibition of cell proliferation, and down-regulated the phosphorylation of signal transducer and activator of transcription 6 (STAT6), an important mediator of IL-13 signaling. i.v. delivery of AdsIL-13Ralpha2 in NOD/SCID mice with s.c. implanted HDLM-2 cells delayed tumor onset and growth while enhancing survival compared with control mice. Intratumoral administration of AdsIL-13Ralpha2 led to the regression or stabilization of established tumors and was associated with diminished STAT6 phosphorylation. Our data demonstrate that AdsIL-13Ralpha2 can suppress HL growth in vitro and in vivo.
Trieu
Young
Y
Division of Experimental Therapeutics, Toronto General Research Institute, McLaughlin Centre for Molecular Medicine, Toronto, Ontario, Canada.
Wen
Xiao-Yan
XY
Skinnider
Brian F
BF
Bray
Mark R
MR
Li
Zhihua
Z
Claudio
Jaime O
JO
Masih-Khan
Esther
E
Zhu
Yuan-Xiao
YX
Trudel
Suzanne
S
McCart
J Andrea
JA
Mak
Tak W
TW
Stewart
A Keith
AK
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics*; D053660:Receptors, Interleukin-13; D050800:STAT6 Transcription Factor; D012995:Solubility; D015534:Trans-Activators / Q000378:metabolism
C508183:Il13ra1 protein, mouse; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators