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Abstract
BackgroundRecognition of lipopolysaccharide (LPS) is required for effective defense against invading gram-negative bacteria. Recently, in vitro studies revealed that CD14 is required for activation of the myeloid differentiation factor (MyD)88-dependent Toll-like receptor (TLR)4 signaling pathway by smooth (S)-LPS, but not by rough (R)-LPS. The present study investigated the role of CD14 in induction of lung inflammation in mice by these different LPS chemotypes.Methodology/ResultsNeutrophil accumulation and tumor necrosis factor (TNF) release in bronchoalveolar lavage fluid were determined 6 hours after intranasal treatment of wild type (WT) and CD14 knock-out (KO) mice with different doses S-LPS or R-LPS. The contribution of CD14 to lung inflammation induced by S-LPS or R-LPS depended on the LPS dose. At low doses, S-LPS and R-LPS induced neutrophil influx in a CD14-dependent manner. Low dose S-LPS-induced cytokine release also depended on CD14. Strikingly, neutrophil influx and TNF release induced by high dose S-LPS or R-LPS was diminished in the presence of CD14. Intranasal administration of sCD14 to CD14 KO mice treated with S-LPS partially reversed the inflammatory response to the response observed in WT mice.ConclusionsIn conclusion, CD14 modulates effects of both S-LPS and R-LPS within the lung in a similar way. Except for R-LPS-induced TNF release, S-LPS and R-LPS at low dose induced acute lung inflammation in a CD14-dependent manner, while the inflammatory response triggered by high dose S-LPS or R-LPS was diminished by CD14.
Highlights
Recognition of endotoxin or LPS, a major constituent of the outer membrane of gram-negative bacteria, has been extensively studied to clarify the mechanisms by which this component activates the immune system [1]
Except for RLPS-induced tumor necrosis factor (TNF) release, S-LPS and R-LPS at low dose induced acute lung inflammation in a CD14-dependent manner, while the inflammatory response triggered by high dose S-LPS or R-LPS was diminished by CD14
Considering that CD14 is a co-receptor within the TLR4 receptor complex, we first investigated whether S-LPS or R-LPS administered intranasally to mice signals through TLR4
Summary
Recognition of endotoxin or LPS, a major constituent of the outer membrane of gram-negative bacteria, has been extensively studied to clarify the mechanisms by which this component activates the immune system [1]. LPS is bound by MD-2 within the TLR4/MD-2 complex [3] and subsequent conformational changes in TLR4 lead to reorganization of its cytoplasmic domain, enabling the recruitment of the adaptors MyD88 and Toll/interleukin 1 receptor domaincontaining adaptor inducing interferon beta (TRIF) [4]. These adaptors initiate signal transduction to the nucleus leading to production of cytokines and chemokines that regulate inflammatory cells [4]. In vitro studies revealed that CD14 is required for activation of the myeloid differentiation factor (MyD)88dependent Toll-like receptor (TLR) signaling pathway by smooth (S)-LPS, but not by rough (R)-LPS. The present study investigated the role of CD14 in induction of lung inflammation in mice by these different LPS chemotypes
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