Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1.
Interleukin-13 (IL-13) is a novel T-cell-derived cytokine with IL-4-like effects on many cell types. In human B lymphocytes, IL-13 induces activation, stimulates proliferation in combination with anti-IgM or anti-CD40 antibodies, and directs Ig isotype switching towards IgE and IgG4 isotypes. We show here that IL-13 also regulates human B-cell apoptosis. IL-13 reduced spontaneous apoptosis of peripheral blood B cells in vitro, as shown by measurement of DNA fragmentation using the TUNEL and Nicoletti assays. The inhibition of cell death by IL-13 alone was significant but modest, but was potently enhanced in combination with CD40 ligand (CD40L), a survival stimulus for B cells by itself. Interestingly, IL-13 increased the expression of CD40 on peripheral blood B cells, providing a possible mechanism for the observed synergy. IL-13 alone was a less potent inhibitor of apoptosis than IL-4. Moreover, there was no additive effect of combining IL-4 and IL-13 at supraoptimal concentrations, which is consistent with the notion that the IL-4 and IL-13 binding sites share a common signaling subunit. The combination of IL-13 with CD40L augmented the expression of the Bcl-2 homologues Bcl-xL and Mcl-1, suggesting this as a possible intracellular mechanism of induced survival. By contrast, levels of Bcl-2, and two other Bcl-2 family members, Bax and Bak, remained unaltered. Given the importance of the CD40-CD40L interaction in B-cell responses, these results suggest a significant role of IL-13 in the regulation of B-cell apoptosis.
Lømo
J
J
Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo.
Blomhoff
H K
HK
Jacobsen
S E
SE
Krajewski
S
S
Reed
J C
JC
Smeland
E B
EB
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D023201:CD40 Ligand; D002478:Cells, Cultured; D003864:Depression, Chemical; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000494:pharmacology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D018793:Interleukin-13; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D023201:CD40 Ligand