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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
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Tumor necrosis factor-α pathway plays a critical role in regulating interferon-γ induced protein-10 production in

Y S Fang1, L M Zhu, Z G Sun

  • 1Department of Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, P.R. China.

Transplantation Proceedings
|May 9, 2012
PubMed

T-cell infiltration of allografts is a major pathologic component defining acute rejection episodes (ARE). We have shown that monocytes interact with allogeneic endothelial cells (ECs) for costimulation to achieve T-cell allorecognition. However, the production of T-cell interferon-γ induced protein-10 (IP-10) and regulation of this chemokine during the initial monocyte-EC interaction are unclear. We hypothesized that the tumor necrosis factor (TNF)-α pathway plays a key role to regulate IP-10 production during the initial monocyte-EC interaction. Cytokine-activated ECs were analyzed for IP-10 production and adhesion molecule expression. Established, monocyte-EC cocultures were analyzed using real-time polymerase chain reaction and a chemokine assay for IP-10 and activation factors. Anti-TNF-α antibody was used to neutralize TNF-α release during monocyte-EC interactions. TNF-α-activated ECs upregulated CD62E and CD54 as determined by flow cytometry, releasing high levels of IP-10 and interleukin (IL)-6. Interferon-γ-stimulated ECs also produced high levels of IP-10 and IL-6. Monocyte-EC interactions demonstrated upregulation of gene transcripts for TNF-α, IL-6, and IP-10. The cytokine/chemokine assay detected high levels of TNF-α, IL-6, and IP-10 in coculture supernates in a time-dependent manner. Anti-TNF-α antibody dramatically reduced IP-10 production by monocyte-ECs interactions. However, anti-TNF-α antibody did not prevent the release of IL-6 by monocytes in EC cocultures. Our results showed that ECs activated by TNF-α are an important source of IP-10. The monocyte-EC interaction produces high levels of IP-10. The TNF-α pathway plays a key role to regulate IP-10 production during monocyte-EC interactions. We thus proposed that the initial monocyte-EC interaction with increased expression of IP-10 may play a critical role to initiate and augment T-cell-mediated ARE.

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