p43 induces IP-10 expression through the JAK-STAT signaling pathway in HMEC-1 cells

Wang,Wei; Tan,Junjie; Xing,Yuhua; Kan,Naipeng; Ling,Jingyi; Dong,Guifu; Liu,Gang; Chen,Huipeng

doi:10.3892/ijmm.2016.2710

p43 induces IP-10 expression through the JAK-STAT signaling pathway in HMEC-1 cells

Authors:
- Wei Wang
- Junjie Tan
- Yuhua Xing
- Naipeng Kan
- Jingyi Ling
- Guifu Dong
- Gang Liu
- Huipeng Chen
View Affiliations

Affiliations: Beijing Institute of Biotechnology, Beijing 100071, P.R. China, National Institutes for Food and Drug Control, Beijing 100071, P.R. China, School of Life Sciences, Anhui University, Hefei, Anhui 230039, P.R. China
Published online on: August 19, 2016 https://doi.org/10.3892/ijmm.2016.2710
Pages: 1217-1224

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

p43 is a cofactor of aminoacyl-tRNA synthetase in mammals that effectively inhibits angiogenesis. However, the role of p43 in angiogenesis remains unclear. In the present study, we examined the effects of p43 on angiogenesis using human microvascular endothelial cells-1 (HMEC-1) cells as a model. Our microarray data showed that p43 regulated a number of cytokines, and the majoity of these are involved in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. IP-10 was previously shown to inhibit angiogenesis and suppress tumor growth via the JAK-STAT signaling pathway in vitro and in vivo. Our results showed that p43 induces both the mRNA and protein expression of IP-10. Furthermore, we demonstrated that p43 exerted an effect on the JAK-STAT signaling pathway by regulating key factors of the pathway. Using a JAK inhibitor, AG490, we studied the effect of p43 on HMEC-1 cells by blocking the JAK-STAT pathway. We found that AG490 inhibited the induction of IP-10 expression by p43, and suppressed the inhibitory effect of p43 on tubule formation and cell migration in HMEC-1 cells. We concluded that p43 inhibits tubule formation and cell migration by inducing IP-10 through the JAK-STAT signaling pathway, and blocking the JAK-STAT pathway with AG490 diminishes the inhibitory effects of p43 on angiogenesis.

View Figures

View References

1	Bdolah Y, Sukhatme VP and Karumanchi SA: Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights. Semin Nephrol. 24:548–556. 2004. View Article : Google Scholar : PubMed/NCBI
2	Bussolino F, Mantovani A and Persico G: Molecular mechanisms of blood vessel formation. Trends Biochem Sci. 22:251–256. 1997. View Article : Google Scholar : PubMed/NCBI
3	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
4	Bouck N, Stellmach V and Hsu SC: How tumors become angiogenic. Adv Cancer Res. 69:135–174. 1996. View Article : Google Scholar : PubMed/NCBI
5	Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med. 6:389–395. 2000. View Article : Google Scholar : PubMed/NCBI
6	Goldmann E: The growth of malignant disease in man and the lower animals, with special reference to the vascular system. Proc R Soc Med. 1(Surg Sect): 1–13. 1908.PubMed/NCBI
7	Algire GH and Legallais FY: Vascular reactions of normal and malignant tissues in vivo. IV. The effect of peripheral hypotension on transplanted tumors. J Natl Cancer Inst. 12:399–421. 1951.PubMed/NCBI
8	Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
9	Quevillon S, Agou F, Robinson JC and Mirande M: The p43 component of the mammalian multi-synthetase complex is likely to be the precursor of the endothelial monocyte-activating polypeptide II cytokine. J Biol Chem. 272:32573–32579. 1997. View Article : Google Scholar
10	Renault L, Kerjan P, Pasqualato S, Ménétrey J, Robinson JC, Kawaguchi S, Vassylyev DG, Yokoyama S, Mirande M and Cherfils J: Structure of the EMAPII domain of human aminoacyl-tRNA synthetase complex reveals evolutionary dimer mimicry. EMBO J. 20:570–578. 2001. View Article : Google Scholar : PubMed/NCBI
11	Otani A, Slike BM, Dorrell MI, Hood J, Kinder K, Ewalt KL, Cheresh D, Schimmel P and Friedlander M: A fragment of human TrpRS as a potent antagonist of ocular angiogenesis. Proc Natl Acad Sci USA. 99:178–183. 2002. View Article : Google Scholar : PubMed/NCBI
12	Kao J, Fan YG, Haehnel I, Brett J, Greenberg S, Clauss M, Kayton M, Houck K, Kisiel W, Seljelid R, et al: A peptide derived from the amino terminus of endothelial-monocyte-activating polypeptide II modulates mononuclear and polymorphonuclear leukocyte functions, defines an apparently novel cellular interaction site, and induces an acute inflammatory response. J Biol Chem. 269:9774–9782. 1994.PubMed/NCBI
13	Park H, Park SG, Lee JW, Kim T, Kim G, Ko YG and Kim S: Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways. J Leukoc Biol. 71:223–230. 2002.PubMed/NCBI
14	Norcum MT and Warrington JA: The cytokine portion of p43 occupies a central position within the eukaryotic multisynthetase complex. J Biol Chem. 275:17921–17924. 2000. View Article : Google Scholar : PubMed/NCBI
15	Behrensdorf HA, van de Craen M, Knies UE, Vandenabeele P and Clauss M: The endothelial monocyte-activating polypeptide II (EMAP II) is a substrate for caspase-7. FEBS Lett. 466:143–147. 2000. View Article : Google Scholar : PubMed/NCBI
16	Shalak V, Kaminska M, Mitnacht-Kraus R, Vandenabeele P, Clauss M and Mirande M: The EMAPII cytokine is released from the mammalian multisynthetase complex after cleavage of its p43/proEMAPII component. J Biol Chem. 276:23769–23776. 2001. View Article : Google Scholar : PubMed/NCBI
17	Wakasugi K and Schimmel P: Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J Biol Chem. 274:23155–23159. 1999. View Article : Google Scholar : PubMed/NCBI
18	Rosen HR, Moroz C, Reiner A, Stierer M, Svec J, Reinerova M, Schemper M and Jakesz R: Expression of p43 in breast cancer tissue, correlation with prognostic parameters. Cancer Lett. 67:35–45. 1992. View Article : Google Scholar : PubMed/NCBI
19	Park H, Park SG, Kim J, Ko YG and Kim S: Signaling pathways for TNF production induced by human aminoacyl-tRNA synthetase-associating factor, p43. Cytokine. 20:148–153. 2002. View Article : Google Scholar
20	Park SG, Kang YS, Ahn YH, Lee SH, Kim KR, Kim KW, Koh GY, Ko YG and Kim S: Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis. J Biol Chem. 277:45243–45248. 2002. View Article : Google Scholar : PubMed/NCBI
21	Ko YG, Park H, Kim T, Lee JW, Park SG, Seol W, Kim JE, Lee WH, Kim SH, Park JE and Kim S: A cofactor of tRNA synthetase, p43, is secreted to up-regulate proinflammatory genes. J Biol Chem. 276:23028–23033. 2001. View Article : Google Scholar : PubMed/NCBI
22	Chang SY, Park SG, Kim S and Kang CY: Interaction of the C-terminal domain of p43 and the alpha subunit of ATP synthase. Its functional implication in endothelial cell proliferation. J Biol Chem. 277:8388–8394. 2002. View Article : Google Scholar
23	Luster AD, Unkeless JC and Ravetch JV: Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 315:672–676. 1985. View Article : Google Scholar : PubMed/NCBI
24	Neville LF, Mathiak G and Bagasra O: The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev. 8:207–219. 1997. View Article : Google Scholar
25	Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD and Strieter RM: CXC chemokines in angiogenesis. J Leukoc Biol. 68:1–8. 2000.PubMed/NCBI
26	Strieter RM, Burdick MD, Gomperts BN, Belperio JA and Keane MP: CXC chemokines in angiogenesis. Cytokine Growth Factor Rev. 16:593–609. 2005. View Article : Google Scholar : PubMed/NCBI
27	Rosenkilde MM and Schwartz TW: The chemokine system - a major regulator of angiogenesis in health and disease. APMIS. 112:481–495. 2004. View Article : Google Scholar : PubMed/NCBI
28	Xing YH, Liu DT, Tan JJ, Hu LD, Liu G, Fu XQ and Chen HP: Construction and screening of truncated mutants of recombinant human anti-angiogenic protein proEMAP/p43. Prog Biochem Biophys. 41:567–574. 2014.
29	Staton CA, Stribbling SM, Tazzyman S, Hughes R, Brown NJ and Lewis CE: Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Pathol. 85:233–248. 2004. View Article : Google Scholar : PubMed/NCBI
30	Park SG, Jung KH, Lee JS, Jo YJ, Motegi H, Kim S and Shiba K: Precursor of pro-apoptotic cytokine modulates aminoacylation activity of tRNA synthetase. J Biol Chem. 274:16673–16676. 1999. View Article : Google Scholar : PubMed/NCBI
31	Lee YS, Han JM, Kang T, Park YI, Kim HM and Kim S: Antitumor activity of the novel human cytokine AIMP1 in an in vivo tumor model. Mol Cells. 21:213–217. 2006.PubMed/NCBI
32	Wilks AF and Oates AC: The JAK/STAT pathway. Cancer Surv. 27:139–163. 1996.PubMed/NCBI
33	Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC and Herman JG: SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 28:29–35. 2001. View Article : Google Scholar : PubMed/NCBI
34	Lin TS, Mahajan S and Frank DA: STAT signaling in the pathogenesis and treatment of leukemias. Oncogene. 19:2496–2504. 2000. View Article : Google Scholar : PubMed/NCBI
35	Yu CL and Burakoff SJ: Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation. J Biol Chem. 272:14017–14020. 1997. View Article : Google Scholar : PubMed/NCBI
36	Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F, Pellegrini S, Yasukawa K, Heinrich P, Stark GR, et al: A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 14:1421–1429. 1995.PubMed/NCBI