Cytokine production by dendritic cells genetically engineered to express IL-4: induction of Th2 responses and differential regulation of IL-12 and IL-23 synthesis.
Dendritic cells (DCs) retrovirally transduced with IL-4 have recently been shown to inhibit murine collagen-induced arthritis and associated Th1 immune responses in vivo, but the mechanisms that underly these effects are not yet understood. In this report we demonstrate that IL-4-transduced DCs loaded with antigen led to lower T cell production of IFN-gamma, increased production of IL-4, and an attenuated, delayed type hypersensitivity response. We hypothesized that the ability of such DCs to regulate the Th1 immune response in vivo depends in part on their capacity to produce IL-12 and IL-23. Quantitative mRNA analysis revealed that IL-4-transduced DCs stimulated with CD40 ligand expressed higher levels of IL-12p35 mRNA, but lower levels of mRNA for IL-23p19 and the common subunit p40 found in both IL-12 and IL-23, compared with control DCs. These results, which indicate that expression of the IL-12 and IL-23 subunits is differentially regulated in IL-4-transduced DCs, were confirmed by ELISA of the IL-12 and IL-23 heterodimers. Thus, therapeutic suppression of Th1 -mediated autoimmunity (as recently shown in murine collagen-induced arthritis) and induction of Th2 responses in vivo by IL-4-transduced DCs occurs despite their potential to produce increased levels of IL-12, but could reflect, in part, decreased production of IL-23.
Morita
Yoshitaka
Y
Division of Nephrology and Rheumatology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.
Gupta
Raj
R
Seidl
Kelly M
KM
McDonagh
Kevin T
KT
Fox
David A
DA
D000818:Animals; D001854:Bone Marrow Cells; D023201:CD40 Ligand / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018014:Gene Transfer Techniques; D006433:Hemocyanins / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000378:metabolism; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin