Mechanistic Insights into CpG DNA and IL-15 Synergy in Promoting B Cell Chronic Lymphocytic Leukemia Clonal Expansion
| Autor: | Patricia K. A. Mongini, Jonathan E. Kolitz, Nicholas Chiorazzi, Jacqueline C. Barrientos, Rashmi Gupta, Xiao J. Yan, Steven L. Allen, Kanti R. Rai |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Immunology Article 03 medical and health sciences Downregulation and upregulation medicine Immunology and Allergy Humans Cell Proliferation Interleukin-15 Messenger RNA Chemistry Drug Synergism medicine.disease Ligand (biochemistry) Leukemia Lymphocytic Chronic B-Cell In vitro Leukemia 030104 developmental biology CpG site Oligodeoxyribonucleotides Interleukin 15 Cancer research Female Lymph Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 201(5) |
| ISSN: | 1550-6606 |
| Popis: | Malignant cell growth within patients with B cell chronic lymphocytic leukemia (B-CLL) is largely restricted to lymphoid tissues, particularly lymph nodes. The recent in vitro finding that TLR-9 ligand (oligodeoxynucleotide [ODN]) and IL-15 exhibit strong synergy in promoting B-CLL growth may be particularly relevant to growth in these sites. This study shows IL-15–producing cells are prevalent within B-CLL–infiltrated lymph nodes and, using purified B-CLL cells from blood, investigates the mechanism for ODN and IL-15 synergy in driving B-CLL growth. ODN boosts baseline levels of phospho-RelA(S529) in B-CLL and promotes NF-κB–driven increases in IL15RA and IL2RB mRNA, followed by elevated IL-15Rα and IL-2/IL-15Rβ (CD122) protein. IL-15→CD122 signaling during a critical interval, 20 to 36–48 h following initial ODN exposure, is required for optimal induction of the cycling process. Furthermore, experiments with neutralizing anti–IL-15 and anti-CD122 mAbs indicate that clonal expansion requires continued IL-15/CD122 signaling during cycling. The latter is consistent with evidence of heightened IL2RB mRNA in the fraction of recently proliferated B-CLL cells within patient peripheral blood. Compromised ODN+IL-15 growth with limited cell density is consistent with a role for upregulated IL-15Rα in facilitating homotypic trans IL-15 signaling, although there may be other explanations. Together, the findings show that ODN and IL-15 elicit temporally distinct signals that function in a coordinated manner to drive B-CLL clonal expansion. |
| Databáze: | OpenAIRE |
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