MDA-7/IL-24 is a unique cytokine-tumor suppressor in the IL-10 Family

Sunil Chada, R. Bryan Sutton, Suhendan Ekmekcioglu, Julie Ellerhorst, John B. Mumm, Wolfgang W. Leitner, Heng Yin Yang, Aysegul A. Sahin, Kelly K. Hunt, Kerry L. Fuson, Nancy Poìndexter, Jack A. Roth, Rajagopal Ramesh, Elizabeth A. Grimm, Abner M. Mhashilkar

Research output: Contribution to journalReview articlepeer-review

130 Scopus citations

Abstract

The melanoma differentiation associated gene-7 (mda-7) cDNA was isolated by virtue of being induced during melanoma differentiation. Initial gene transfer studies convincingly demonstrated potent antitumor effects of mda-7. Further studies showed that the mechanism of antitumor activity was due to induction of apoptosis. Most striking was the tumor-selective killing by mda-7 gene transfer - normal cells were unaffected by Adenoviral delivery of mda-7 (Ad-mda7). A variety of molecules implicated in apoptosis and intracellular signaling are regulated by Ad-mda7 transduction. Different apoptosis effector proteins are regulated in different tumor types, suggesting that Ad-mda7 may regulate various signaling pathways. mda-7 encodes a secreted protein, MDA-7, which has now been designated as IL-24, and is a novel member of the IL-10 cytokine family. MDA-7/IL-24 protein is actively secreted from cells after mda-7 gene transfer. In human peripheral blood mononuclear cells (PBMC), STAT3 activation by MDA-7/IL-24 is followed by elaboration of secondary Th1 cytokines, demonstrating that MDA-7/IL-24 is a pro-Th1 cytokine. Furthermore, MDA-7/IL-24 is antagonized by the prototypic Th2 cytokine IL-10. MDA-7/IL-24 protein is endogenously expressed in cultured NK and B-cells and is also expressed in dendritic cells in tissues. MDA-7/IL-24 protein is expressed in nevi and melanoma primary tumors, to varying degrees, but is rarely expressed in malignant melanoma or other human tumors evaluated. Indeed, loss of MDA-7/IL-24 protein expression correlates strongly with melanoma tumor invasion and disease progression. The "bystander" effects proposed for MDA-7/IL-24 protein include immune stimulation, antiangiogenesis and receptor-mediated cytotoxicity. Thus, mda-7 is a unique multifunctional cytokine in the IL-10 family and may have potent antitumor utility in a clinical setting.

Original languageEnglish (US)
Pages (from-to)649-667
Number of pages19
JournalInternational Immunopharmacology
Volume4
Issue number5
DOIs
StatePublished - May 2004

Keywords

  • Angiogenesis
  • Apoptosis
  • Cancer
  • IL-10
  • IL-24
  • mda-7

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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