Submitted on July 24, 2007
Accepted on March 25, 2008
IL-4 and IL-13 upregulate ornithine decarboxylase expression by PI3K and MAP kinase pathways in vascular smooth muscle cells
Liu Hua Wei1, Yang Yang2, Guoyao Wu3, and Louis J Ignarro4*
1 Pharmacology, UCLA, Los Angeles, California, United States
2 California Institute of Technology, Pasadena, California, United States
3 Animal Science, Texas A&M University, College Station, Texas, United States
4 Pharmacology, University of California. Los Angeles, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: lignarro{at}mednet.ucla.edu.
Ornithine decarboxylase (ODC) is the first and rate-controlling enzyme in the synthesis of polyamines, which are essential for normal cell growth. We have previously demonstrated that IL-4 and IL-13 can stimulate rat aortic smooth muscle cell (RASMC) proliferation. The objective of this study was to determine if IL-4 and IL-13 induce cell proliferation by upregulating ODC expression in RASMC. The results revealed that incubation of RASMC with IL-4 and IL-13 for 24 h caused 4-5 fold induction of ODC catalytic activity. The increased ODC catalytic activity was attributed to the increased expression of ODC mRNA. Moreover, these observations were paralleled by increased production of polyamines. We further investigated the signal transduction pathways responsible for ODC induction by IL-4 and IL-13. The data illustrated that PD 98059, a MEK (MAPK kinase) inhibitor, LY 294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor and H-89, a protein kinase A (PKA) inhibitor substantially decreased the induction of ODC catalytic activity and ODC mRNA expression induced by IL-4 and IL-13, suggesting positive regulation of the ODC gene by ERK, PI3K and PKA pathways. Interestingly, dexamethasone, a known inhibitor of cell proliferation, completely abrogated the response of RASMC to IL-4 and IL-13. Furthermore, the inhibition of ODC by these inhibitors led to the reduced production of polyamines and decreased DNA synthesis as monitored by [3H] thymidine incorporation. Our data indicate that upregulation of ODC by IL-4 and IL-13 might play an important role in the pathophysiology of vascular disorders characterized by excessive smooth muscle growth.
