The Pseudomonas aeruginosa HSP90-like protein HtpG regulates IL-8 expression through NF-κB/p38 MAPK and CYLD signaling triggered by TLR4 and CD91

Abstract

Pulmonary infection activates acute inflammatory responses by recruiting neutrophils to the infection site; this recruitment is promoted by interleukin-8 (IL-8). However, IL-8 production in response to Pseudomonas aeruginosa HtpG (PA1596), a homolog of heat shock protein 90, has yet not been characterized in detail. htpG expression in P. aeruginosa strain was elevated upon infection of host cells, and HtpG was released into bacterial culture supernatant. Treatment of dTHP-1 macrophages with recombinant HtpG (rHtpG) increased production of IL-8 in a dose- and time-dependent manner, and this effect was abolished by inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) p38 signaling. By contrast, the rHtpG-mediated production of IL-8 was increased by suppression of cylindromatosis (CYLD), suggesting that CYLD is a negative regulator of this pathway. The upregulation of expression was coordinated by signals transmitting through toll-like receptor 4 (TLR4) with the aid of CD91. Together, these observations suggest that P. aeruginosa HtpG activates NF-κB, CYLD, and p38 MAPK in a TLR4-and CD91-dependent manner, leading to stimulation of IL-8 production in macrophages.

Keywords: CYLD; HtpG; IL-8; NF-κB; Pseudomonas aeruginosa; p38.