IL-4 is a mediator of IL-12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells.
IL-12 is a key inducer of Th1-associated inflammatory responses, protective against intracellular infections and cancer, but also involved in autoimmune tissue destruction. We report that human Th2 cells interacting with monocyte-derived dendritic cells (DC) effectively induce bioactive IL-12p70 and revert to Th0/Th1 phenotype. In contrast, the interaction with B cells preserves polarized Th2 phenotype. The induction of IL-12p70 in Th2 cell-DC cocultures is prevented by IL-4-neutralizing mAb, indicating that IL-4 acts as a Th2 cell-specific cofactor of IL-12p70 induction. Like IFN-gamma, IL-4 strongly enhances the production of bioactive IL-12p70 heterodimer in CD40 ligand-stimulated DC and macrophages and synergizes with IFN-gamma at low concentrations of both cytokines. However, in contrast to IFN-gamma, IL-4 inhibits the CD40 ligand-induced production of inactive IL-12p40 and the production of either form of IL-12 induced by LPS, which may explain the view of IL-4 as an IL-12 inhibitor. The presently described ability of IL-4 to act as a cofactor of Th cell-mediated IL-12p70 induction may allow Th2 cells to support cell-mediated immunity in chronic inflammatory states, including cancer, autoimmunity, and atopic dermatitis.
Department of Cell Biology and Histology and Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. KalinskiP@msx.upmc.edu
P
P
Kaliński
H H
HH
Smits
J H
JH
Schuitemaker
P L
PL
Vieira
M
M
van Eijk
E C
EC
de Jong
E A
EA
Wierenga
M L
ML
Kapsenberg
D000276:Adjuvants, Immunologic / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology; D015847:Interleukin-4 / Q000502:physiology*; D008024:Ligands; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma