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.
Kaliński
P
P
Department of Cell Biology and Histology and Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. KalinskiP@msx.upmc.edu
Smits
H H
HH
Schuitemaker
J H
JH
Vieira
P L
PL
van Eijk
M
M
de Jong
E C
EC
Wierenga
E A
EA
Kapsenberg
M L
ML
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