Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming.
Leptin is an adipocyte-derived hormone/cytokine that links nutrition, metabolism, and immune homeostasis. Leptin is capable of modulating several immune responses. However, the effect of leptin on dendritic cells (DCs) has not yet been recognized. Because DCs are instrumental in the development of immune responses, in this study, we evaluated the impact of leptin on DC activation. We demonstrated the presence of leptin receptor in human immature and mature DCs both at mRNA and protein level and its capacity to transduce leptin signaling leading to STAT-3 phosphorylation. We found no consistent modulation of DC surface molecules known to be critical for their APC function in response to leptin. In contrast, we found that leptin induces rearrangement of actin microfilaments, leading to uropod and ruffle formation. At a functional level, leptin up-regulates the IL-1beta, IL-6, IL-12, TNF-alpha, and MIP-1alpha production. Coincident with this, leptin-treated DCs stimulate stronger heterologous T cell responses. Furthermore, we found that leptin down-regulates IL-10 production by DCs and drives naive T cell polarization toward Th1 phenotype. Finally, we found that leptin partly protects DCs from spontaneous and UVB-induced apoptosis. Consistent with the antiapoptotic effect of leptin, we observed the activation of NF-kappaB and a parallel up-regulation of bcl-2 and bcl-x(L) gene expression. These results provide new insights on the immunoregulatory function of leptin demonstrating its ability to improve DC functions and to promote DC survival. This is of relevance considering a potential application of leptin in immunotherapeutic approaches and its possible use as adjuvant in vaccination protocols.
Mattioli
Benedetta
B
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Straface
Elisabetta
E
Quaranta
Maria Giovanna
MG
Giordani
Luciana
L
Viora
Marina
M
D008841:Actin Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D000276:Adjuvants, Immunologic / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D048430:Cell Shape / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D016130:Immunophenotyping; D020738:Leptin / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology; D054411:Receptors, Leptin; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D051020:bcl-X Protein
D000276:Adjuvants, Immunologic; C494811:BCL2L1 protein, human; D018925:Chemokines; D016207:Cytokines; C515448:LEPR protein, human; D020738:Leptin; D016328:NF-kappa B; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D051020:bcl-X Protein