IRF4 silencing inhibits Hodgkin lymphoma cell proliferation, survival and CCL5 secretion.
Interferon regulatory factor 4 (IRF4) expression is detected in many lymphoid and myeloid malignancies, and may be a promising therapeutic target. IRF4 is strongly expressed in classical Hodgkin lymphoma (cHL) and its expression is up-regulated by CD40L and down-regulated by both anti-proliferative and pro-apoptotic stimuli. This study analysed the effects of IRF4 silencing in a panel of HL-derived cell lines. We demonstrated that IRF4 down-modulation determined a remarkable decrease of both cell number and clonogenic growth in L-1236, L-428, KM-H2 and HDLM-2 cells, but not in IRF4-negative L-540 cells. IRF4 silencing induced apoptosis, as evaluated by caspase-3 activation and Annexin-V staining and up-regulation of the pro-apoptotic molecule Bax. CD40 engagement by both soluble and membrane bound-CD40L almost totally reduced IRF4 down-modulation and growth inhibition by IRF4 silencing in both L-1236 and L-428 cells. Finally, IRF4 silencing decreased CCL5 secretion in all HL cell lines tested and CCL17 in KM-H2 cells. Taken together, our results demonstrated that IRF4 down-modulation by IRF4 silencing was reversed by CD40 engagement, inhibited HL cells proliferation, induced apoptosis and decreased CCL5 secretion, thus suggesting that IRF4 may be involved in HL pathobiology.
Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, Italy. daldinucci@cro.it
Donatella
D
Aldinucci
Marta
M
Celegato
Cinzia
C
Borghese
Alfonso
A
Colombatti
Antonino
A
Carbone
D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D018946:Chemokine CCL5 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000099218:Interferon Regulatory Factor-4
D019013:CD40 Antigens; D018946:Chemokine CCL5; D016207:Cytokines; D050835:Interferon Regulatory Factors; D009363:Neoplasm Proteins; D000099218:Interferon Regulatory Factor-4; C483024:CCL5 protein, human