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

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.

• Authors: 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
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 4 Issue 5 Pg. 649-67 (May 2004) ISSN: 1567-5769 [Print] Netherlands
• PMID: 15120650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Cytokines
• Interleukins
• interleukin-24
• Interleukin-10

Topics

• Cytokines (classification, genetics, pharmacology)
• Genes, Tumor Suppressor (drug effects)
• Humans
• Interleukin-10 (classification, genetics, pharmacology)
• Interleukins (classification, genetics, pharmacology)