Submitted on November 16, 2005
Revised on May 12, 2006
Hypoxia-induced Mitogenic Factor Promotes VCAM-1 Expression via PI-3k/Akt-NF-
B Signaling Pathway
Qiangsong Tong1, Liduan Zheng2, Li Lin3, Bo Li1, Danming Wang1, and Dechun Li1*
1 Department of Internal Medicine, St. Louis University, St. Louis, MO, USA,
2 Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,
3 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: dli2{at}slu.edu.
Hypoxia-induced mitogenic factor (HIMF), also known as FIZZ1 (found in inflammatory zone 1), is an important player in lung inflammation. However, the effects of HIMF on cell adhesion molecules involved in lung inflammation remain largely unknown. In this present work, we tested whether HIMF modulates vascular adhesion molecule-1 (VCAM-1) expression, and dissected the possible signaling pathways that link HIMF to VCAM-1 upregulation. Recombinant HIMF protein instilled intratracheally into adult mouse lungs results in a significant increase of VCAM-1 production in vascular endothelial cells, alveolar type II and airway epithelial cells. In cultured mouse endothelial SVEC 4-10 and lung epithelial MLE-12 cells, we demonstrated that HIMF induces VCAM-1 expression via the PI-3K-Akt/NF-
B signaling pathway. Knockdown of HIMF expression by siRNA attenuated LPS-induced VCAM-1 expression in vitro. We showed that HIMF induced phosphorylation of the IKK signalsome and subsequently, IB
, leading to activation of NF-B. Meanwhile, VCAM-1 production was correspondingly upregulated. Blocking NF-B signaling pathway by expression of dominant-negative mutants of IKK and IB suppressed HIMF-induced VCAM-1 upregulation. HIMF also strongly induced phosphorylation of Akt. A dominant-negative mutant of PI-3K, 
p85, as well as PI-3K inhibitor LY294002, also blocked HIMF-induced NF-B activation and attenuated VCAM-1 production. Furthermore, LY294002 pretreatment abolished HIMF-enhanced mononuclear cells adhesion to endothelial and epithelial cells. Our findings connect HIMF to signaling pathways that regulate inflammation, and thus reveal the critical roles that HIMF plays in lung inflammation.
