Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis.

Abstract

Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFκB p65 cascade was performed by Western blot. The secretion of cytokines IL-1β, IL-6, IL-10 and TNFα was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFκB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1β, IL-6, IL-10 and TNFα was induced by silica exposure and the induction of IL-1β, IL-6 and TNFα was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFκB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis.

• Authors: Judy Yuet Wa Chan, Joseph Chi Ching Tsui, Patrick Tik Wan Law, Winnie Kwok Wei So, Doris Yin Ping Leung, Michael Mau Kwong Sham, Stephen Kwok Wing Tsui, Carmen Wing Han Chan
• Journal: International journal of medical sciences (Int J Med Sci) Vol. 15 Issue 10 Pg. 986-991 ( 2018) ISSN: 1449-1907 [Electronic] Australia
• PMID: 30013439 (Publication Type: Journal Article)

Chemical References

• Interleukin-1beta
• TLR4 protein, human
• Toll-Like Receptor 4
• Silicon Dioxide

Topics

• Humans
• Inflammation (chemically induced)
• Interleukin-1beta
• Macrophages
• Signal Transduction
• Silicon Dioxide (adverse effects)
• Silicosis (metabolism)
• Toll-Like Receptor 4 (metabolism)