A TLR4-interacting SPA4 peptide inhibits LPS-induced lung inflammation

作者：Ramani Vijay; Madhusoodhanan Rakhesh; Kosanke Stanley; Awasthi Shanjana^*

来源：Innate Immunity, 2013, 19(6): 596-610.

DOI：10.1177/1753425912474851

• Inflammation
• surfactant protein-A
• Toll-like receptor-4
• host defense
• protein-protein interaction

The interaction between surfactant protein-A (SP-A) and TLR4 is important for host defense. We have recently identified an SPA4 peptide region from the interface of SP-A-TLR4 complex. Here, we studied the involvement of the SPA4 peptide region in SP-A-TLR4 interaction using a two-hybrid system, and biological effects of SPA4 peptide in cell systems and a mouse model. HEK293 cells were transfected with plasmid DNAs encoding SP-A or a SP-A-mutant lacking SPA4 peptide region and TLR4. Luciferase activity was measured as the end-point of SP-A-TLR4 interaction. NF-B activity was also assessed simultaneously. Next, the dendritic cells or mice were challenged with Escherichia coli-derived LPS and treated with SPA4 peptide. Endotoxic shock-like symptoms and inflammatory parameters (TNF-, NF-B, leukocyte influx) were assessed. Our results reveal that the SPA4 peptide region contributes to the SP-A-TLR4 interaction and inhibits the LPS-induced NF-B activity and TNF-. We also observed that the SPA4 peptide inhibits LPS-induced expression of TNF-, nuclear localization of NF-B-p65 and cell influx, and alleviates the endotoxic shock-like symptoms in a mouse model. Our results suggest that the anti-inflammatory activity of the SPA4 peptide through its binding to TLR4 can be of therapeutic benefit.

• 出版日期2013-12