Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion.
Several cytokines have been suggested to play a regulatory action on the neoplastic clone of patients with B-cell chronic lymphocytic leukemia (B-CLL) by interfering in the differentiation, proliferation, or death/survival pathways. Interleukin-8 (IL-8) is a chemoattractant protein constitutively expressed at the mRNA level and released by B-CLL cells. In view of the presence of the IL-8 receptor mRNA and of specific IL-8 binding, confirmed also by Scatchard analysis using 125I-IL-8, the study was extended to evaluate the possible regulatory role of this cytokine on B-CLL cells. IL-8 failed to show any in vitro proliferative effect on leukemic B-CLL cells. By contrast, the propidium iodide (PI) staining of the DNA content showed that IL-8 could prolong the survival of resting B-CLL cells in 11 of 16 cases studied. In the remaining 5 cases, 90.6% +/- 4.39% SD of the cells after culture remained viable and IL-8 could exert a significant death protection action after pretreatment with 10(-4) mol/L hydrocortisone, which reduced the percentage of viable B-CLL cells. The dose range of IL-8 capable of inducing the prolonging survival effect is comparable with the levels of IL-8 released constitutively by B-CLL cells, indicating that the death protection action is exerted at physiologic doses. The in vitro rescue from death induced by IL-8 is reflected by an increased expression of bcl-2 mRNA in B-CLL cases incubated in the presence of IL-8. These findings were further confirmed at the protein level, because in B-CLL cells that displayed a bimodal bcl-2 intracytoplasmatic protein expression IL-8 was capable of upmodulating the bcl-2high expression peak. The potential autocrine regulatory action exerted by IL-8 is supported by the evidence that exogenous IL-8 can upregulate IL-8 mRNA in B-CLL cells. These results, together with the demonstration that antibody-mediated neutralization of endogenous IL-8 could induce a significant in vitro reduction in the number of living cells, further support the hypothesis that, in B-CLL, the physiologic doses of IL-8 released constitutively by the leukemic clone may play an autocrine role in the process of cell accumulation characteristic of this disease.
Francia di Celle
P
P
Dipartimento di Scienze Biomediche e Oncologia Umana, University of Torino, Italy.
Mariani
S
S
Riera
L
L
Stacchini
A
A
Reato
G
G
Foa
R
R
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D023062:Receptors, Interleukin-8A; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D016209:Interleukin-8; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A