IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival.
Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-kappaB activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8- dependent survival pathway.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Inbal
I
Binsky
Michal
M
Haran
Diana
D
Starlets
Yael
Y
Gore
Frida
F
Lantner
Nurit
N
Harpaz
Lin
L
Leng
David M
DM
Goldenberg
Lev
L
Shvidel
Alain
A
Berrebi
Richard
R
Bucala
Idit
I
Shachar
D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D016209:Interleukin-8; C045084:invariant chain