The regulation of inflammatory liver responses by the TNF ligand and receptor system-TWEAK and Fn14, via human intra-hepatic endothelial cells

Munir, Mamoona (2015). The regulation of inflammatory liver responses by the TNF ligand and receptor system-TWEAK and Fn14, via human intra-hepatic endothelial cells. University of Birmingham. Ph.D.

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Abstract

TWEAK (TNF-like weak inducer of apoptosis) and Fn14 (FGF-inducible protein 14) are TNF (tumour necrosis factor) superfamily members which have multifunctional capabilities. They have been shown to regulate inflammation, angiogenesis, cell fate, and tumourigenesis. They have recently been shown to contribute to hepatic inflammatory responses and regeneration during liver insult and chronic inflammatory liver disease (CILD). We propose that TWEAK and Fn14 may regulate CILD via human intra-hepatic endothelial cells (HIEC) and subsequently be developed in future as novel therapeutic agents towards CILD. Our investigation showed that TWEAK was predominantly expressed in leukocyte infiltrates in CILD tissue, it was highly regulated by interferon-γ in leukocytes, and contributed directly towards leukocyte recruitment via HIEC. Fn14 expression in CILD tissue was expressed in endothelium and portal vessels, and Fn14 expression was highly regulated by TNF-α and interleukin-1β in HIEC. We showed that TWEAK can directly contribute to angiogenesis in the inflamed liver via HIEC, by orchestrating a specific angiogenic cytokine response, and that TWEAK and Fn14 may contribute to portal-associated lymphoid tissue formation. We further found that TWEAK mediated functions via HIEC were highly regulated via NF-kB and Erk signalling, and that TWEAK can directly mediate HIEC reactive oxygen specie production and responses to necrosis. We can conclude from our findings that TWEAK and Fn14 may regulate CILD by complex signal transduction, and specifically mediate the inflammatory angiogenic responses by adopting paracrine mechanisms; whereby Fn14 is endogenously expressed in HIEC, and TWEAK and Fn14 interactions during CILD are facilitated by TWEAK positive leukocyte infiltration.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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