Nasal Challenge with LPS Stimulates the Release of Macrophage Inflammatory Protein 1α

Abstract

Background: Bacterial infections can cause a variety of airway diseases. Toll-like receptors (TLRs) directly respond to the presence of microbes and partake in the innate immune defense. TLR4 is activated by lipopolysaccharide (LPS), and has been detected in sinonasal tissue, epithelial cells and various inflammatory cells. Macrophage inflammatory protein 1α (MIP-1α) is a chemokine released during the inflammatory process. The present study investigated the potential role and regulation of MIP-1α in LPS-induced nasal inflammation. Methods: Thirty-two healthy individuals were intranasally challenged with LPS or vehicle. Nasal lavage was performed, followed by a nasal biopsy. Inflammatory cells were counted, MIP-1α levels analyzed and expression of MIP-1α mRNA in biopsies quantified. Neutrophils isolated from peripheral blood were treated with LPS and effects on MIP-1α release, cell survival, and the involved signal pathways, were investigated. Results: LPS challenge caused an increase of MIP-1α in nasal lavage. No corresponding change in mRNA expression was seen in nasal biopsies, suggesting the increase was not due to epithelial synthesis. Neutrophil numbers increased after LPS provocation. Treatment of isolated neutrophils with LPS delayed neutrophil apoptosis and resulted in a time- and concentration-dependent release of MIP-1α, which was reduced by inhibitors of transcription and of nuclear factor (NF)-κB, protein kinase C (PKC) and p38 MAPK pathways. Conclusions: Nasal LPS challenge results in release of MIP-1α. The release most likely originates from recruited neutrophils, via NF-κB-, PKC- and p38 MAPK-dependent pathways. LPS stimulation delayed neutrophil apoptosis. MIP-1α may constitute an important mediator in neutrophilic airway disease.

Intranasal Administration of poly(I:C) and LPS in BALB/c Mice Induces Airway Hyperresponsiveness and Inflammation via Different Pathways

“…Detection of microbes by TLRs evokes an inflammatory response. We, along with several other research groups, have demonstrated functionally active TLRs in nearly all cell types implicated in the pathogenesis of asthma and allergic airway disease, including eosinophils, neutrophils, mast cells, monocytes, dendritic cells, macrophages, B-cells, T-cells, epithelial cells and smooth muscle cells [6], [7], [8], [9], [10], [11]. Accordingly, several TLRs and TLR ligands have been associated with the development of asthma [12].…”

Regulation of Constitutive Neutrophil Apoptosis Due to House Dust Mite Allergen in Normal and Allergic Rhinitis Subjects

“…The anti-apoptotic downstream mechanism that occurs via TLR4 activated by DP is involved in the PKCδ/ERK/NF-κB pathway (Figure 3 and 6). Ekman et al demonstrated that LPS activates the PKCδ/p38 MAPK/NF-κB pathway via TLR4 in nasal neutrophils and Kilpatrick et al reported that TNF-α suppresses neutrophil apoptosis via the PKCδ/ERK pathway [9], [28], [29]. These reports indicate that anti-apoptotic signaling molecules associated with DP are important to anti-apoptotic signaling in response to other stimulators in neutrophils.…”

Systemic Up-Regulation of TLR4 Causes Lipopolysaccharide-Induced Augmentation of Nasal Cytokine Release in Allergic Rhinitis

“…This might partly be related to the applied doses of allergen and LPS, but also to the low number of patients examined. Along with several groups, we have shown that challenge with allergen, but not LPS, can cause local nasal symptoms [23] and that both allergen and LPS have the ability to release an array of cytokines in the nose [23,24,25,26,27,28,29]. …”