Interferon γ-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells

Elizabeth D. Feldman, David M. Weinreich, Nancy M. Carroll, Monika L. Burness, Andrew L Feldman, Ewa Turner, Hui Xu, H. Richard Alexander

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background: Interferon γ-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. Methods: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. Results: IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was > 40 in HUVECs, compared with ≤10 in the other cell types. Moreover, CXCR3B mRNA levels were significantly higher in proliferating compared with confluent HUVECs. In vivo, systemic IP-10 administration resulted in slower A375 xenograft growth rates compared with control-treated animals, and immunohistochemical staining showed decreased microvessel density in xenografts of IP-10-treated mice. Conclusions: IP-10 has antiangiogenic properties and selective effects on endothelial tissue that may be secondary to higher levels of the CXCR3B inhibitory/proapoptotic receptor in that cell type, particularly in its actively proliferating state.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalAnnals of Surgical Oncology
Volume13
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Chemokine CXCL10
Human Umbilical Vein Endothelial Cells
Endothelial Cells
Apoptosis
Fibroblasts
Proteins
Messenger RNA
Tumor Cell Line
Heterografts
Melanoma
Microvessels
Reverse Transcriptase Polymerase Chain Reaction
Recombinant Proteins
Vascular Endothelial Growth Factor A
Endothelium
Adenocarcinoma
Cell Count
Staining and Labeling
Ligands
T-Lymphocytes

Keywords

  • A375 melanoma
  • Angiogenesis
  • CXCR3
  • Endothelium
  • Interferon γ-inducible protein 10

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Interferon γ-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells. / Feldman, Elizabeth D.; Weinreich, David M.; Carroll, Nancy M.; Burness, Monika L.; Feldman, Andrew L; Turner, Ewa; Xu, Hui; Alexander, H. Richard.

In: Annals of Surgical Oncology, Vol. 13, No. 1, 01.2006, p. 125-133.

Research output: Contribution to journalArticle

Feldman, ED, Weinreich, DM, Carroll, NM, Burness, ML, Feldman, AL, Turner, E, Xu, H & Alexander, HR 2006, 'Interferon γ-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells', Annals of Surgical Oncology, vol. 13, no. 1, pp. 125-133. https://doi.org/10.1245/ASO.2006.03.038
Feldman, Elizabeth D. ; Weinreich, David M. ; Carroll, Nancy M. ; Burness, Monika L. ; Feldman, Andrew L ; Turner, Ewa ; Xu, Hui ; Alexander, H. Richard. / Interferon γ-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells. In: Annals of Surgical Oncology. 2006 ; Vol. 13, No. 1. pp. 125-133.
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abstract = "Background: Interferon γ-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. Methods: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. Results: IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was > 40 in HUVECs, compared with ≤10 in the other cell types. Moreover, CXCR3B mRNA levels were significantly higher in proliferating compared with confluent HUVECs. In vivo, systemic IP-10 administration resulted in slower A375 xenograft growth rates compared with control-treated animals, and immunohistochemical staining showed decreased microvessel density in xenografts of IP-10-treated mice. Conclusions: IP-10 has antiangiogenic properties and selective effects on endothelial tissue that may be secondary to higher levels of the CXCR3B inhibitory/proapoptotic receptor in that cell type, particularly in its actively proliferating state.",
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AU - Weinreich, David M.

AU - Carroll, Nancy M.

AU - Burness, Monika L.

AU - Feldman, Andrew L

AU - Turner, Ewa

AU - Xu, Hui

AU - Alexander, H. Richard

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AB - Background: Interferon γ-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. Methods: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. Results: IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was > 40 in HUVECs, compared with ≤10 in the other cell types. Moreover, CXCR3B mRNA levels were significantly higher in proliferating compared with confluent HUVECs. In vivo, systemic IP-10 administration resulted in slower A375 xenograft growth rates compared with control-treated animals, and immunohistochemical staining showed decreased microvessel density in xenografts of IP-10-treated mice. Conclusions: IP-10 has antiangiogenic properties and selective effects on endothelial tissue that may be secondary to higher levels of the CXCR3B inhibitory/proapoptotic receptor in that cell type, particularly in its actively proliferating state.

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