Fibroblast growth factor-inducible 14 (Fn14) is expressed in the lower genital tract and may play a role in amplifying inflammation during infection

Abstract

TNF-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor (TNF) cytokine superfamily which regulates a number of cellular responses, including inflammation and proliferation. TWEAK is primarily secreted by phagocytic cells and its receptor, fibroblast growth factor-inducible 14 (Fn14), is expressed on non-lymphoid cells, including epithelial, endothelial and mesenchymal cells. The TWEAK/Fn14 pathway is highly conserved from an evolutionary standpoint, and has been shown to play a role in tissue regeneration and inflammation in the liver, kidney, lung and skeletal muscle. We hypothesized that TWEAK/Fn14 might have a physiological role in regulating infection-induced inflammation in the lower female genital tract. To test this hypothesis, we examined expression of the receptor Fn14 in relevant cells and tissue. Receptor function was tested by treating cells with recombinant TWEAK, with and without other known proinflammatory stimuli. Flow cytometric analysis of vaginal and cervical epithelial cells revealed that Fn14 was highly expressed at the cell surface. We also detected both Fn14 and TWEAK in whole cervical tissue by RT-PCR. Treatment of vaginal and cervical epithelial cells with recombinant TWEAK led to a weak induction of the chemokine IL-8. However, TWEAK potentiated the effects of IL-1ß, the TLR2 ligand Pam 3 CysSK 4 , and live Neisseria gonorrhoeae in a synergistic manner. These data reveal a novel pathway for regulation of microbial-induced inflammation in the female reproductive tract and suggest that interference with the TWEAK/Fn14 pathway might be an approach to abrogate excessive infection-induced inflammation caused by sexually transmitted pathogens.

The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases; focus on inflammatory bowel diseases

“…TWEAK cooperates with IL-17 to augment inflammatory mediator expression in HeLa cells (T. Hamilton, personal communication, January 16, 2009), analogous to the cooperation between TNF-␣ and IL-17 [69]. TWEAK also potentiates the pro-inflammatory effects of TLR ligands, synergizing with Pam 3 CysSK 4 for the stimulation of IL-8 production by epithelial cells [70] and with oxidized-LDL for the production of MCP-1 and RANTES by vascular smooth muscle cells and a renal proximal tubule cell line [71]. In addition, TWEAK-induced RANTES was synergistically augmented by TGF-␤ in human keratinocyte cultures [31].…”

“…The ability of bacterial components and inflammatory cytokines to induce the expression of Fn14 is another important aspect of the feed-forward loop, promoting the accumulation of immune effector cells and substances. In addition, it has been reported that TWEAK augments stimulation with TLR ligands, synergizing with Pam 3 CysSK 4 for stimulation of IL-8 production in the case of urogenital epithelial cells [70]. Further, TWEAK cooperates with IL-17, an inflammatory cytokine up-regulated in CD, to augument inflammatory mediator expression in Hela cells (T. Hamilton, personal communication, January 16, 2009), analogous to the cooperation between TNF-␣ and IL-17 [69,105].…”

Fn14 Receptor Appears as a Modulator Of Ovarian Steroid‐Related Regulation Of Goat Endometrial Epithelial Cell IL‐18 expression

“…However, regulation of Fn14 expression in the genital tract in general remains unclear. Although hormonal signals are unlikely to be required for Fn14 receptor expression on the genital tract epithelial cells as reported previously, regulation of Fn14 receptor expression by hormonal changes is still a possibility. In the present study, distinct effects of E 2 and/or P 4 on the regulation of both Fn14 mRNA and protein expression by goat EECs were observed in the presence and absence of ESCs.…”

“…On top of this, they must maintain the ability to respond to pathogenic microorganisms and other dangers that might be encountered at this site. A number of in vitro and in vivo studies suggest that the TWEAK/Fn14 interaction may play a role in regulating inflammation within tissues . Given its reported effects on cell proliferation and cell survival, TWEAK/Fn14 axis may be also play a role in response to cyclic hormonal changes, during pregnancy, and other physiologic conditions .…”

“…The activation of the TWEAK/Fn14 pathway is highly controlled by the inducible expression of Fn14 receptor . Expression of Fn14 is well documented in cells of epithelial origin such as bronchus, lower genital tract, and intestinal epithelium . The expression of Fn14 is known to be highly inducible by a variety of cytokines, including IL‐13, TNF‐α, as well as by its own ligand TWEAK .…”