NFAT1 mediates placental growth factor-induced myelomonocytic cell recruitment via the induction of TNF-alpha.

Abstract

Recruitment of bone marrow-derived myelomonocytic cells plays a fundamental role in tumor angiogenesis and metastasis. Placental growth factor (PlGF) is a potent cytokine that can attract myelomonocytic cells to the tumor. However, the underlying mechanism remains obscure. In this study, we demonstrate that tumor-derived PlGF activates NFAT1 via vascular endothelial growth factor receptor 1 in both murine and human myelomonocytic cells. Activation of NFAT1 is crucial for PlGF-induced myelomonocytic cell recruitment as shown by the in vitro transwell migration assay, transendothelial migration assay, and PlGF-overexpressing tumor models in mice, respectively. TNF-alpha is upregulated by PlGF in myelomonocytic cells in an NFAT1-dependent manner, which in turn contributes to PlGF-induced myelomonocytic cell recruitment. Blockade of TNF-alpha expression by RNA interference or neutralization of secreted TNF-alpha with its Ab attenuates PlGF-induced myelomonocytic cell migration and transendothelial migration. Furthermore, the inhibitory effect of NFAT1 RNA interference on PlGF function is rescued by exogenously added TNF-alpha. Taken together, we demonstrate that NFAT1 mediates PlGF-induced myelomonocytic cell recruitment via the induction of TNF-alpha. Our present studies discover a novel role of the NFAT1-TNF-alpha pathway in tumor inflammation, which may provide potential targets to diversify current cancer therapy.

• Authors: Yanping Ding, Yujie Huang, Nan Song, Xiaobin Gao, Shaopeng Yuan, Xiaofeng Wang, Hongchen Cai, Yan Fu, Yongzhang Luo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 5 Pg. 2593-601 (Mar 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20097868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NFATC Transcription Factors
• Oligopeptides
• PGF protein, human
• Pgf protein, mouse
• Pregnancy Proteins
• Tumor Necrosis Factor-alpha
• VIVIT peptide
• Placenta Growth Factor
• Cyclosporine
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cyclosporine (pharmacology)
• Fluorescent Antibody Technique
• Humans
• Immunoblotting
• Mice
• Mice, Inbred C57BL
• Monocytes (cytology, metabolism)
• Myeloid Cells (cytology, metabolism)
• NFATC Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Oligopeptides (pharmacology)
• Placenta Growth Factor
• Pregnancy Proteins (genetics, metabolism)
• RNA Interference
• Transfection
• Transplantation, Heterologous
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (genetics, metabolism)