Neutrophil elastase up‐regulates interleukin‐8 via toll‐like receptor 4

Devaney, James; Greene, Catherine M.; Taggart, Clifford C.; Carroll, Tomás P.; O’Neill, Shane; McElvaney, Noel G.

doi:10.1016/s0014-5793(03)00482-4

Cited by 214 publications

(155 citation statements)

References 25 publications

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“…Their primary function is to degrade and kill engulfed microorganisms in the phagolysosome; however, these molecules also participate in extracellular matrix degradation, tissue remodelling, proteolysis of surfactant proteins, activation of matrix metalloproteinases, proteolytic cleavage of cytokines and receptors and cell signalling. 26 NE can aggravate inflammation a number of ways, which include increasing the release of IL-8 through stimulation of TLR4, 27 stimulating goblet cell degranulation, mucus hypersecretion leading to airflow obstruction. 28 29 Plasma levels of NE have not been investigated previously in asthma phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

Baines

Simpson

Wood

et al. 2011

Thorax

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Section: Discussionmentioning

confidence: 99%

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

Baines

Simpson

Wood

et al. 2011

Thorax

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“…Based on the reports of the mediation of the proinflammatory effects of some proteases through TLR4 (65)(66)(67), the role of proteolytic cleavage of the TLR4 ectodomain for receptor activation remains to be thoroughly examined. We could, however, not detect cell activation of TLR4-transfected HEK293 cells by elastase, which has been reported previously (67).…”

Section: Discussionmentioning

confidence: 99%

The Ectodomain of the Toll-like Receptor 4 Prevents Constitutive Receptor Activation

Panter

Jerala

2011

Journal of Biological Chemistry

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Toll-like receptor 4 (TLR4) is involved in activation of the innate immune response in a large number of different diseases.Despite numerous studies, the role of separate domains of TLR4 in the regulation of receptor activation is poorly understood. Replacement of the TLR4 ectodomain with LPS-binding proteins MD-2 or CD14 resulted in a robust ligand-independent constitutive activation comparable with the maximal stimulation of the receptor with LPS. The same effect was achieved by the replacement of the ectodomain with a monomeric fluorescent protein or a 24-kDa gyrase B fragment. This demonstrates an intrinsic dimerization propensity of the transmembrane and cytoplasmic domains of TLR4 and reveals a previously unknown function of the ectodomain in inhibiting spontaneous receptor dimerization. Constitutive activation was abolished by the replacement of the ectodomain by a bulkier protein ovalbumin. N-terminal deletion variants of TLR4 revealed that the smallest segment of the ectodomain that already prevents constitutive activity comprises only 90 residues (542 to 631) of the total 608 residues. We conclude that TLR4 represents a receptor with a low threshold of activation that can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. The TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization.Pattern recognition receptors are proteins expressed by cells of the innate immune system and act as a first line of host defense against invading microorganisms, recognizing diverse but highly conserved structural pathogen-associated molecular patterns of bacteria, fungi, and viruses (1). Activation of pattern recognition receptors by their respective ligands triggers an immediate immune response, characterized by proinflammatory cytokine production (1, 2). Toll-like receptors (TLRs) 2 are a family of pattern recognition receptors central to the vertebrate innate immune response. Activation of TLRs links innate and adaptive immunity through proinflammatory signaling and induction of costimulatory molecules on immune cells (3, 4). However, activation of TLRs has to be a tightly regulated process. TLRs have to be able to mount an immediate immune response upon binding of the agonist, whereas in the absence of the ligand it is imperative that they remain in an inactive state to prevent unwanted activation that may lead to excessive inflammation and autoimmune disease (5). This is especially important for TLR4, the cellular receptor for LPS, a molecular signature of the outer cell membrane of Gram-negative bacteria (6). Activation of TLR4 by LPS affects the regulation of more than 1000 genes (7). Additionally, TLR4 signaling has been implicated in sterile inflammation through activation of the receptor by endogenous ligands (8 -14).TLR4 is a type I transmembrane glycoprotein. The ectodoma...

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“…NE contributes to the altered ASL composition in CF by activating the apical epithelial sodium channel which increases sodium uptake from the ASL (Caldwell et al, 2005). NE also aggravates neutrophilic inflammation in CF by upregulating epithelial expression of a major neutrophil chemokine, IL-8 (Nakamura et al, 1992, Devaney et al, 2003. IL-8 increases NE release from CF neutrophils (Taggart et al, 2000) resulting in a self-perpetuating cycle of neutrophil inflammation and excessive NE in ASL.…”

Section: Neutrophil Elastasementioning

confidence: 99%

“…IL-8 increases NE release from CF neutrophils (Taggart et al, 2000) resulting in a self-perpetuating cycle of neutrophil inflammation and excessive NE in ASL. NE transcriptionally upregulates IL-8 by two mechanisms: activation of TLR4 resulting in signaling via MyD88 and IRAK (Devaney et al, 2003) and EGFR transactivation and signaling via p38 MAPK (Kuwahara et al, 2006). NE indirectly increases IL-8 by cleaving CXCR1, an IL-8 receptor on neutrophils, and the soluble CXCR1 fragment activates TLR2 on airway epithelia increasing the transcription of IL-8 .…”

Section: Neutrophil Elastasementioning

confidence: 99%

Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways leading to bronchiectasis and respiratory failure. The signature pathologic features of CF lung disease including abnormal mucus obstructing airways, chronic infection with S. aureus, P. aeruginosa and other gram negative bacteria, and a robust neutrophil-dominant airway inflammation, are exacerbated by unopposed proteases present at high concentrations in the ASL. There is strong evidence that proteases, particularly neutrophil elastase, contribute to the pathology of CF by impairing mucociliary clearance, interfering with innate immune functions, and perpetuating neutrophilic inflammation. The mechanisms employed by proteases to impact airway function in CF will be reviewed.

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Neutrophil elastase up‐regulates interleukin‐8 via toll‐like receptor 4

Cited by 214 publications

References 25 publications

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

The Ectodomain of the Toll-like Receptor 4 Prevents Constitutive Receptor Activation

Proteases and cystic fibrosis

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