CBER Research Projects

Project Title

Identification and Characterization of Novel Interleukin-10-Related Genes

Principal Investigator

R. P. Donnelly

Laboratory

Laboratory of Immunology; Division of Therapeutic Proteins; Office of Therapeutics Research and Review

Project Summary

Activation of human monocytes by bacterial endotoxin, lipopolysaccharide (LPS), induces expression of many cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6 and IL-10. IL-10 expression is delayed relative to that of TNF, IL-1 and IL-6. Furthermore, IL-10 feedback inhibits expression of TNF, IL-1 and IL-6, thus providing an efficient autocrine mechanism for controlling proinflammatory cytokine production in monocytes.

In this project, we are examining the mechanism by which IL-10 down-regulates production of cytokines such as TNF and IL-1 in endotoxin-stimulated monocytes. We are also evaluating the effects of IL-10 on signal transduction events that are activated by cytokines such as IFN-gamma (IFN-g) and IL-4. We have found that IL-10 inhibits activation and gene expression induced by IL-4 and IFN-gamma. We have also determined that the ability of IL-10 to inhibit IL-4-inducible gene expression is a consequence of decreased tyrosine phosphorylation and nuclear translocation of the IL-4-inducible transcription factor, STAT6. We are now examining the role of a novel family of JAK/STAT inhibitory genes, the Suppressors of Cytokine Signaling (SOCS) genes, in mediating these IL-10-inducible inhibitory effects. We have found that IL-10 selectively induces expression of one member of this newly identified gene family, SOCS-3. Forced expression of SOCS-3 in a macrophage cell line markedly inhibits induction of STAT activity by several cytokines, including IFN-gamma, GM-CSF and IL-4. Therefore, the ability of IL-10 to antagonize cytokine-inducible gene expression appears to be associated with its ability to induce rapid expression of the SOCS-3 gene.

In related studies, we are also examining the biological activities of several newly identified IL-10 homologues. One of these, IL-19, shares approximately 21% amino acid homology with IL-10, and may utilize at least one of the two receptor chains that form the functional IL-10 receptor complex. We have found that expression of the IL-19 gene is upregulated by many of the same agents that induce IL-10 gene expression in monocytes. However, unlike the IL-10 gene, IL-19 is not expressed in activated T cells. Another IL-10 homologue, IL-TIF (IL-10-related T cell-derived inducible factor), has also recently been described. Together with scientists at the University of Medicine & Dentistry of New Jersey (UMDNJ), we have identified and characterized the gene encoding the ligand-binding chain of the receptor for this novel IL-10-related cytokine, IL-TIF. This receptor chain heterodimerizes with the IL-10R-beta chain (IL-10R2) to form a functional IL-TIF receptor complex. Therefore, IL-10R2 is component of both the IL-10 and IL-TIF receptors. We have recently found that the IL-TIF receptor is expressed at high levels in liver and kidney, but not in hematopoietic tissues such as the spleen and thymus. This suggests a possible functional role for this receptor in regulating gene expression in these tissues.

Publications

• J Immunol 1998 Apr 15;160(8):4048-56
  Involvement of the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of human monocyte and macrophage proinflammatory mediator production.
  Bonder CS, Dickensheets HL, Finlay-Jones JJ, Donnelly RP, Hart PH
  Pub Med

• Blood 1999 Mar 1;93(5):1456-63
  Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1.
  Ito S, Ansari P, Sakatsume M, Dickensheets H, Vazquez N, Donnelly RP, Larner AC, Finbloom DS
  Pub Med

• J Leukoc Biol 1999 Mar;65(3):307-12
  Inhibition of IL-4-inducible gene expression in human monocytes by type I and type II interferons.
  Dickensheets HL, Donnelly RP
  Pub Med

• J Interferon Cytokine Res 1999 Jun;19(6):563-73
  The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes.
  Donnelly RP, Dickensheets H, Finbloom DS
  Pub Med

• Eur J Immunol 1999 Jul;29(7):2087-97
  Diminished responses to IL-13 by human monocytes differentiated in vitro: role of the IL-13Ralpha1 chain and STAT6.
  Hart PH, Bonder CS, Balogh J, Dickensheets HL, Vazquez N, Davies KV, Finlay-Jones JJ, Donnelly RP
  Pub Med

• Proc Natl Acad Sci U S A 1999 Sep 14;96(19):10800-10805
  Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression.
  Dickensheets HL, Venkataraman C, Schindler U, Donnelly RP
  Pub Med

• Genes Immunity 2000 Oct;1(7):442-50
  Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10).
  Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD, Vazquez N, Pestka S, Donnelly RP, Kotenko SV
  Pub Med

• J Biol Chem 2001 Jan 26;276(4):2725-2732
  Identification of the functional IL-TIF (IL-22) receptor complex: the IL-10R2 chain (IL-10R{beta}) is a shared component of both IL-10 and IL-TIF (IL-22) receptor complexes.
  Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S
  Pub Med

• J Immunol 2001 Jun 15;166(12):7096-7103
  Identification, Cloning, and Characterization of a Novel Soluble Receptor That Binds IL-22 and Neutralizes Its Activity.
  Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S
  Pub Med

Last Updated: 4/1/2002

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Date created: September 25, 2003

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