Interleukin-4 distinctively modifies responses of germinal centre-like and activated B-cell-like diffuse large B-cell lymphomas to immuno-chemotherapy.
Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively. In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes. We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes. Herein, we demonstrated that IL-4 increased the sensitivity of GCB-like DLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing. In contrast, IL-4 protected ABC-like DLBCL from the cytotoxic effects of doxorubicin and rituximab. The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-like DLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes. These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-like DLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.
Sarosiek
Kristopher A
KA
Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
Nechushtan
Hovav
H
Lu
Xiaoqing
X
Rosenblatt
Joseph D
JD
Lossos
Izidore S
IS
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D000069283:Rituximab; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D000069283:Rituximab; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases
Blood. 2000 Jun 15;95(12):3900-8
10845926
Mol Cell Biol. 2007 Mar;27(6):2166-79
17210636
Clin Cancer Res. 2006 Jul 1;12(13):4027-35
16818702
Cell. 1997 Sep 19;90(6):1073-83
9323135
J Immunol Methods. 2001 Dec 1;258(1-2):183-91
11684135
Leuk Lymphoma. 2007 Jul;48(7):1290-8
17613756
J Clin Oncol. 2006 Jul 1;24(19):3121-7
16754935
Cell Immunol. 2001 Aug 1;211(2):131-42
11591117
N Engl J Med. 2002 Jan 24;346(4):235-42
11807147
Blood. 2008 Nov 15;112(10):4098-108
18716132
Blood. 2001 Sep 1;98(5):1352-7
11520782
Blood. 2006 Apr 15;107(8):3205-11
16373664
Blood. 2006 Dec 15;108(13):4178-86
16946303
J Clin Oncol. 2008 Jan 20;26(3):447-54
18086797
J Clin Oncol. 2003 Apr 15;21(8):1466-71
12697868
J Immunol. 2003 Aug 15;171(4):1722-31
12902471
Nature. 2000 Feb 3;403(6769):503-11
10676951
N Engl J Med. 2002 Jun 20;346(25):1937-47
12075054
N Engl J Med. 2004 Apr 29;350(18):1828-37
15115829
Br J Haematol. 2001 Dec;115(4):807-11
11843813
J Exp Med. 2001 Dec 17;194(12):1861-74
11748286
Leuk Lymphoma. 2002 Jun;43(6):1313-21
12153001
Cell Res. 2007 Nov;17(11):942-55
17968425
Blood. 2005 May 15;105(10):3979-86
15677569
Blood. 2005 Apr 1;105(7):2924-32
15591113
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10209-13
10954754
Gynecol Oncol. 2004 Sep;94(3):785-95
15350374
Blood. 1990 Mar 1;75(5):1114-8
2306518
FEBS Lett. 1997 Nov 17;417(3):360-4
9409752
Leukemia. 2003 Apr;17(4):789-95
12682639
J Immunother. 2001 May-Jun;24(3):263-71
11394505
Blood. 2002 Apr 1;99(7):2285-90
11895757