The extracellular proteinase Expi/Wfdc18 in liver damage and tumour development: A new connection between inflammation, fibrogenesis and malignant growth

Introduction: Recently we have identified quantitative trait loci (QTLs) that determine susceptibility to TGF-beta signalling in mouse hepatocytes in vitro and fibrogenesis in vivo (Liebe et al. Physiol Genomics 2013). Expi/Wfdc18 candidacy was identified by eQTL and DNA variant analyses. Expi/Wfdc18 knockout animals showed decreased hepatic collagen contents following 6 weeks of CCl4 challenge.

Methods: To assess the function of Expi outside its normal role in mammary gland development and antibacterial defence in salivary glands, we performed an in silico analyses of Expi/Wfdc18 expression and a systematic search for pathobiological roles of WFDC molecules.

Results: GEO microarray data revealed TLR9-mediated induction of Expi/Wfdc18 in RAW 264.7 macrophages by unmethylated CpG (Tross et al. J Immunol 2009). The adjacent Wfdc17/AMWAP peptide (70% amino acid identity) is a negative regulator of macrophage activity in microglia with antibacterial activities (Karlstetter et al. J Immunol. 2011). Expi/Wfdc18 was overexpressed 6- to 20-fold in adenomas from ApcMin/+ mice (Reichling et al. Cancer Res 2005) and increased 4-fold in ErbB2/Neu positive mammary tumours compared to normal control tissue (Landis et al. Oncogene 2005). In humans, WFDC2/HE4 is a serum marker for ovarial and endometrial tumours as well as gastric and pancreatic carcinoma, and has recently been described as a fibroblast-derived mediator of fibrosis in kidney (LeBleu et al. NatMed 2013).

Conclusions: Expi/Wfdc18 increases hepatic fibrogenesis following chronic CCl4 challenge in the mouse. Its expression is induced by TLR9 ligand CpG dinucleotide in macrophages. We conclude that Expi/Wfdc18 is an alarm peptide involved in the TLR9-mediated innate defence against invading microbial pathogens and primes liver cells for pro-apoptotic signals. Expi/Wfdc18 is ectopically overexpressed in murine gastrointestinal and mammary tumours. We suspect that Wfdc18/Expi may play a similar role as WFDC2/HE4. The Expi/Wfdc18 knockout mouse represents a new animal model to study the impact of the innate immune system on fibrogenesis and malignant growth.

Corresponding author: Liebe, Roman

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