MDA-7/IL-24 is a unique cytokine--tumor suppressor in the IL-10 family.
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.
Chada
Sunil
S
Introgen Therapeutics, Inc., 2250 Holcombe Blvd., Houston, TX 77030, USA. s.chada@introgen.com
Sutton
R Bryan
RB
Ekmekcioglu
Suhendan
S
Ellerhorst
Julie
J
Mumm
John B
JB
Leitner
Wolfgang W
WW
Yang
Heng-Yin
HY
Sahin
Aysegul A
AA
Hunt
Kelly K
KK
Fuson
Kerry L
KL
Poìndexter
Nancy
N
Roth
Jack A
JA
Ramesh
Rajagopal
R
Grimm
Elizabeth A
EA
Mhashilkar
Abner M
AM
D016207:Cytokines / Q000145:classification / Q000235:genetics / Q000494:pharmacology*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D016753:Interleukin-10 / Q000145:classification* / Q000235:genetics / Q000494:pharmacology; D007378:Interleukins / Q000145:classification* / Q000235:genetics / Q000494:pharmacology*; D000099180:Interleukin-24
D016207:Cytokines; D016753:Interleukin-10; D007378:Interleukins; D000099180:Interleukin-24