Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-101

IL-10 regulates inflammation by reducing cytokine and chemokine production from activated macrophages. We performed microarray experiments to identify possible effector molecules of IL-10 and to investigate the global effect of IL-10 on the transcriptional response induced in LPS-activated macrophages. To exclude background effects of endogenous IL-10, macrophages from IL-10-deficient mice were used. IL-10 up-regulated expression of a small number of genes (26 and 37 after 45 min and 3 h, respectively), including newly identified and previously documented targets such as suppressor of cytokine signaling-3 and IL-1 receptor antagonist. However, the activation program triggered by LPS was profoundly affected by IL-10. IL-10 repressed 62 and further increased 15 of 259 LPS-induced genes. For all genes examined, the effects of IL-10 were determined to be STAT3-dependent. These results suggest that IL-10 regulates STAT3-dependent pathways that selectively target a broad component of LPS-induced genes at the mRNA level.

[1]  A. Brasier,et al.  NF-κB-inducible BCL-3 Expression Is an Autoregulatory Loop Controlling Nuclear p50/NF-κB1 Residence* , 2001, The Journal of Biological Chemistry.

[2]  H. Pendeville,et al.  SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis , 1999, Cell.

[3]  K Eichmann,et al.  Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. , 1999, Journal of immunology.

[4]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[5]  M. Munder,et al.  Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. , 1998, Journal of immunology.

[6]  D. Pappin,et al.  Activation of MEK‐1 and SEK‐1 by Tpl‐2 proto‐oncoprotein, a novel MAP kinase kinase kinase. , 1996, The EMBO journal.

[7]  J. G. Zhang,et al.  Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Wei Zhang,et al.  Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter , 1995, Molecular and cellular biology.

[9]  H. Dickensheets,et al.  The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[10]  P. Heinrich,et al.  SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal Transduction through the SHP2 Recruitment Site of gp130* , 2000, The Journal of Biological Chemistry.

[11]  Ash A. Alizadeh,et al.  Stereotyped and specific gene expression programs in human innate immune responses to bacteria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. Hurst,et al.  Transcriptional repression by a novel member of the bZIP family of transcription factors , 1992, Molecular and cellular biology.

[13]  H. Dickensheets,et al.  Interleukin-10 Inhibits Expression of Both Interferon – and Interferon γ– Induced Genes by Suppressing Tyrosine Phosphorylation of STAT1 , 1999 .

[14]  Y. Vodovotz,et al.  Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. , 1992, The Journal of biological chemistry.

[15]  R. Schreiber,et al.  Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses , 1998, Cell.

[16]  E. Lander,et al.  Human macrophage activation programs induced by bacterial pathogens , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Flavell,et al.  GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. , 2001, Immunity.

[18]  Y. Liu,et al.  IL‐10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3‐dependent and ‐independent pathways , 1998, The EMBO journal.

[19]  G. Trinchieri,et al.  Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. , 1998, Journal of immunology.

[20]  M. Modolell,et al.  Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines , 1995, European journal of immunology.

[21]  M. Mayo,et al.  Interleukin-10 Signaling Blocks Inhibitor of κB Kinase Activity and Nuclear Factor κB DNA Binding* , 1999, The Journal of Biological Chemistry.

[22]  T. Gotoh,et al.  Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide. , 1999, American journal of physiology. Endocrinology and metabolism.

[23]  P. Rutgeerts,et al.  Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease , 2000 .

[24]  S. Akira,et al.  Interleukin-10 Receptor Signaling through the JAK-STAT Pathway , 1999, The Journal of Biological Chemistry.

[25]  W. Greene,et al.  The Proto-Oncogene Cot Kinase Participates in CD3/CD28 Induction of NF-κB Acting through the NF-κB-Inducing Kinase and IκB Kinases , 1999 .

[26]  George Kollias,et al.  Interleukin‐10 targets p38 MAPK to modulate ARE‐dependent TNF mRNA translation and limit intestinal pathology , 2001, The EMBO journal.

[27]  P. Rutgeerts,et al.  Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. , 2000, Gastroenterology.

[28]  T. Gingeras,et al.  Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. , 2001, The Journal of experimental medicine.

[29]  P. Pavlidis,et al.  Cutting Edge: STAT6 Serves as a Positive and Negative Regulator of Gene Expression in IL-4-Stimulated B Lymphocytes1 , 2002, The Journal of Immunology.

[30]  F. Larminat,et al.  Overexpression of Metallothionein-II Sensitizes Rodent Cells to Apoptosis Induced by DNA Cross-linking Agent through Inhibition of NF-κB Activation* , 2002, The Journal of Biological Chemistry.

[31]  T. van der Poll,et al.  Proinflammatory Effects of IL-10 During Human Endotoxemia1 , 2000, The Journal of Immunology.

[32]  T. Gingeras,et al.  Reprogramming of the Macrophage Transcriptome in Response to Interferon-γ and Mycobacterium tuberculosis , 2001, The Journal of experimental medicine.

[33]  R. Young,et al.  T cell-derived IL-10 antagonizes macrophage function in mycobacterial infection. , 1997, Journal of immunology.

[34]  J. Ihle,et al.  Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production1 , 2001, The Journal of Immunology.

[35]  H. Dickensheets,et al.  Interleukin-10 upregulates tumor necrosis factor receptor type-II (p75) gene expression in endotoxin-stimulated human monocytes. , 1997, Blood.

[36]  K. Heeg,et al.  Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs1 , 2001, The Journal of Immunology.

[37]  W. Alexander,et al.  The SOCS box: a tale of destruction and degradation. , 2002, Trends in biochemical sciences.

[38]  S. Akira,et al.  Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. , 1999, Immunity.

[39]  G. Davis,et al.  Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. , 2000, Gastroenterology.

[40]  G. Kollias,et al.  TNF-α Induction by LPS Is Regulated Posttranscriptionally via a Tpl2/ERK-Dependent Pathway , 2000, Cell.

[41]  R. Donnelly,et al.  Inhibition of IL-10 expression by IFN-gamma up-regulates transcription of TNF-alpha in human monocytes. , 1995, Journal of immunology.

[42]  J. Johnston,et al.  Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. , 1999, Journal of immunology.

[43]  S. Goerdt,et al.  Other functions, other genes: alternative activation of antigen-presenting cells. , 1999, Immunity.

[44]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[45]  I. Udalova,et al.  Evidence for a Dual Mechanism for IL-10 Suppression of TNF-α Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-κB in Primary Human Macrophages1 , 2002, The Journal of Immunology.

[46]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.