Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13.
To understand the modulation of dendritic cell (DC) function by IL-10, gene expression profiling was performed by using Affymetrix technology (Santa Clara, CA) in human monocyte-derived DC treated with IL-10, alone or in combination with LPS. The modulation of selected genes was validated by real-time PCR, Northern blot, and protein production. IL-10 regulated in DC the expression of a limited number of genes, including IL-7, the receptors for transferrin and vitamin D(3), structural matrix proteins, and signal transduction elements. The combined treatment with LPS plus IL-10 modulated a number of genes comparable to LPS alone, but the expression profiles were distinct. As expected, IL-10 suppressed the expression of several LPS-inducible proinflammatory molecules. Among genes uniquely modulated by the concomitant treatment with LPS plus IL-10, phosphatidylinositol 3-kinase gamma was down-regulated while the suppressor of cytokine signaling 3, signaling lymphocytic activation molecule, regulator of G protein signaling 16, and the chemokine, CXC chemokine ligand (CXCL) 13, were up-regulated. Overall, four distinct transcriptional programs were identified, related to: 1) control of immunity and inflammation; 2) tuning of cytokine receptor and G protein-coupled receptor signaling; 3) remodeling of extracellular matrix; and 4) B cell function and lymphoid tissue neogenesis. Among the latter genes, we further demonstrate that IL-10 synergizes with TLR ligands for the production of functionally active B cell-attracting chemokine, CXCL13, in both myeloid and plasmacytoid DC. This novel finding reveals that IL-10 sustains humoral immunity by inducing the production in APCs of the chemokine, CXCL13, which amplifies B cell recruitment and promotes lymphoid tissue neogenesis.
Perrier
Patrick
P
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Martinez
Fernando O
FO
Locati
Massimo
M
Bianchi
Giancarlo
G
Nebuloni
Manuela
M
Vago
Gianluca
G
Bazzoni
Flavia
F
Sozzani
Silvano
S
Allavena
Paola
P
Mantovani
Alberto
A
D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000378:metabolism*; D005136:Eye Proteins / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D020710:RGS Proteins / Q000502:physiology; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation
C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D005136:Eye Proteins; D008070:Lipopolysaccharides; D020710:RGS Proteins; C107413:RGS16 protein; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016753:Interleukin-10