title: Toll-like receptors on B-CLL cells: expression and functional consequences of their stimulation.
abstract: Toll-like receptor (TLR) stimulation plays a crucial role in the homeostasis of human B cells. We investigated the expression of TLRs 1-9 on the cells of B-cell chronic lymphocytic leukemia (B-CLL) and analyzed the functional consequences of TLR stimulation on leukemic cells. We showed that B-CLL cells express similar set of TLRs as memory B cells of healthy donors, i.e. TLR-1, TLR-2, TLR-6, TLR-7 and TLR-9. However, in contrast to memory B cells, B-CLL cells lack TLR-4 expression. Expression of TLRs correlates with their capacity to respond to specific TLR agonists. At the level of phenotype, ODN2006 (TLR-9 agonist) is the most potent stimulus. B-CLL cells also respond to the stimulation with loxoribine, Pam3CSK4 and MALP-2 (TLR-7, TLR1/TLR2 and TLR2/TLR6 agonists, respectively). TLR-7 and TLR-9 stimulation induces production of IL-6 and TNFalpha. In 47% of tested patients, treatment with ODN2006, MALP-2 and Pam3CSK4 reduced leukemic cells survival. Stimulation of B-CLL cells with TLR-9 agonists, loxoribine, MALP-2 and Pam3CSK4 induces significant proliferation. We report that TLR stimulation induces expression of CD38, a negative prognostic marker, on B-CLL cells. Expression of CD38 is induced by direct stimulation of B-CLL cells through TLR-7 and TLR-9 or CD38 can be induced on B-CLL cells indirectly by a soluble factor induced in non-B-CLL cells after stimulation with TLR-2, TLR-3 or TLR-5 agonists; the nature of this factor remains unknown. Our results argue for cautious evaluation of immunointervention strategies based on the administration of TLR agonists in the treatment of B-CLL as their effects on B-CLL cells may be tumor promoting as well as tumor suppressing.
authors.affiliation: Institute of Immunology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic. daniela.rozkova@lfmotol.cuni.cz
authors.forename: Daniela
authors.initials: D
authors.lastname: Rozková
authors.forename: Linda
authors.initials: L
authors.lastname: Novotná
authors.forename: Robert
authors.initials: R
authors.lastname: Pytlík
authors.forename: Ivana
authors.initials: I
authors.lastname: Hochová
authors.forename: Tomás
authors.initials: T
authors.lastname: Kozák
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartůnková
authors.forename: Radek
authors.initials: R
authors.lastname: Spísek
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors; D051997:ADP-ribosyl Cyclase 1