IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells.
Dendritic cells (DCs) play an important role in innate and adaptive immune responses. In addition to their phagocytic activity, DCs present foreign antigens to naïve T cells and regulate the development of adaptive immune responses. Upon contact with DCs, activated T cells produce large quantities of cytokines such as interferon-gamma (IFN-gamma) and interleukin (IL)-21, which have important immunoregulatory functions. Here, we have analyzed the effect of IL-21 and IFN-gamma on lipopolysaccharide (LPS)-induced maturation and cytokine production of human monocyte-derived DCs. IL-21 and IFN-gamma receptor genes were expressed in high levels in immature DCs. Pretreatment of immature DCs with IL-21 inhibited LPS-stimulated DC maturation and expression of CD86 and human leukocyte antigen class II (HLAII). IL-21 pretreatment also dramatically reduced LPS-stimulated production of tumor necrosis factor alpha, IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) but not that of CXCL8. In contrast, IFN-gamma had a positive feedback effect on immature DCs, and it enhanced LPS-induced DC maturation and the production of cytokines. IL-21 weakly induced the expression Toll-like receptor 4 (TLR4) and translation initiation region (TIR) domain-containing adaptor protein (TIRAP) genes, whereas the expression of TIR domain-containing adaptor-inducing IFN-beta (TRIF), myeloid differentiation (MyD88) 88 factor, or TRIF-related adaptor molecule (TRAM) genes remained unchanged. However, IL-21 strongly stimulated the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3 genes. SOCS are known to suppress DC functions and interfere with TLR4 signaling. Our results demonstrate that IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid DCs, providing a negative feedback loop between DCs and T lymphocytes.
Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. mari.strengell@ktl.fi
Mari
M
Strengell
Anne
A
Lehtonen
Sampsa
S
Matikainen
Ilkka
I
Julkunen
D002450:Cell Communication; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins / Q000494:pharmacology* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D053655:Receptors, Interleukin-21; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000096743:Interferon gamma Receptor; D000098546:Interleukin-21
D018946:Chemokine CCL5; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D018664:Interleukin-12; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053655:Receptors, Interleukin-21; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; D000098546:Interleukin-21; C483024:CCL5 protein, human; C508117:IL21R protein, human; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C434984:TIRAP protein, human; C495345:TLR4 protein, human