Abstract
TILRR has been identified as an important modulator of inflammatory responses. It is associated with NF-κB activation, and inflammation. Our previous study showed that TILRR significantly increased the expression of many innate immune responsive genes and increased the production of several pro-inflammatory cytokines/chemokines by cervical epithelial cells. In this study, we evaluated the effect of TILRR-induced pro-inflammatory cytokines/chemokines on the migration of immune cells. The effect of culture supernatants of TILRR-overexpressed cervical epithelial cells on the migration of THP-1 monocytes and MOLT-4 T-lymphocytes was evaluated using Transwell assay and a novel microfluidic device. We showed that the culture supernatants of TILRR-overexpressed HeLa cells attracted significantly more THP-1 cells (11–40%, p = 0.0004–0.0373) and MOLT-4 cells (14–17%, p = 0.0010–0.0225) than that of controls. The microfluidic device-recorded image analysis showed that significantly higher amount with longer mean cell migration distance of THP-1 (p < 0.0001–0.0180) and MOLT-4 (p < 0.0001–0.0025) cells was observed toward the supernatants of TILRR-overexpressed cervical epithelial cells compared to that of the controls. Thus, the cytokines/chemokines secreted by the TILRR-overexpressed cervical epithelial cells attracted immune cells, such as monocytes and T cells, and may potentially influence immune cell infiltration in tissues.
Highlights
Previous studies identified that TILRR (Toll-like/Interleukin-1 receptor regulator), a FREM1 isoform 2, is an important regulator of genes in the NF-κB signal transduction pathway and inflammatory responses (Zhang et al, 2010, 2012)
The results showed that THP-1 monocyte migration was gradually increased with increasing macrophage chemo-attractant protein (MCP)-1/CCL2 concentration, and migration efficiency was gradually decreased to close to baseline level after 50 ng/ml MCP-1/CCL2 (Figure 2A)
The highest percentage of THP-1 cell migration was observed at 50 ng/ml chemokine concentration, and the lowest percentage was with 5 ng/ml of MCP-1/CCL2 using three different cell counting methods
Summary
Previous studies identified that TILRR (Toll-like/Interleukin-1 receptor regulator), a FREM1 isoform 2, is an important regulator of genes in the NF-κB signal transduction pathway and inflammatory responses (Zhang et al, 2010, 2012). We have shown that TILRR modulates expression of many inflammation responsive genes and production of pro-inflammatory cytokines/chemokines such as IL-6, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, MIP1β/CCL4 and RANTES/CCL5 in cervico-vaginal epithelial cells (Kashem et al, 2019). The inflammatory cytokines/chemokines secreted by the TILRR-overexpressed cervical epithelial cells could influence immune cell migration to tissues. Because cervical epithelial cells express FREM1 (Luo et al, 2012), and TILRR overexpression increases the production of pro-inflammatory mediators by cervical epithelial cell lines (Kashem et al, 2019), we hypothesized that the cytokines/chemokines produced by the cervical epithelial cell line may influence the migration and tissue infiltration of immune cells. We report here that the supernatants of TILRR-overexpressed HeLa cells significantly attracted THP-1 (monocyte) and MOLT-4 (Tlymphocyte) cells than the controls
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