Regulation of interleukin-8 via an airway epithelial signaling cascade

Abstract

Airways function as an innate immune organ against airborne bacteria that are inhaled and deposited in airways. One of the mechanisms of host defense is to recruit neutrophils into airways to clear the invaders. Airway epithelial cells produce neutrophil chemoattractant interleukin (IL)-8 in response to invading bacteria. In this study we show a signaling pathway on the plasma surface of human airway epithelial NCI-H292 cells that regulate IL-8 production in response to a model inflammatory stimulus, phorbol 12-myristate 13-acetate, and a pathophysiological stimulus, gram-negative bacterial lipopolysaccharide. First, we show that EGF receptor (EGFR) and MAP kinase ERK1/2 are involved in IL-8 expression by these stimuli. Second, we show that EGFR ligand transforming growth factor (TGF)-α mediates IL-8 production. Third, we show that tumor necrosis factor-α-converting enzyme (TACE) is required for IL-8 production by cleaving EGFR proligand proTGF-α into soluble TGF-α, activating EGFR. Last, we show that dual oxidase 1 (Duox1), a homolog of NADPH oxidase in airways, mediates TACE activation and IL-8 expression via generation of reactive oxygen species. In summary, we describe a signaling pathway, Duox1-TACE-TGF-α-EGFR, on the surface of airway epithelial (NCI-H292) cells that mediates airway epithelial defense against bacterial infection by producing IL-8. This pathway, which also regulates mucin production in human airways, provides mechanisms for killing foreign organisms and for their clearance.

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

“…A similar mechanism was previously implicated in the DUOX2-dependent regulation of NF-κB activity, and the thereof resulting IL-8 production and neutrophil recruitment [45]. The closelyrelated homolog of DUOX2, DUOX1 that is also expressed in AECs was previously shown to regulate EG-FR-dependent signaling [46,47]. Additionally, DUOX1-derived H 2 O 2 was shown to regulate intracellular protein phosphatase activities [48,49].…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Recent studies suggest that DUOX may participate in these responses as well, as illustrated by DUOX1-mediated production of epithelial mucins, such as MUC1 and MUC5AC, in response to inflammatory mediators such as neutrophil elastase or tumor necrosis factor (TNF)-α (105,106). Similarly, DUOX1 also mediates epithelial production of the neutrophil chemokine IL-8 in response to stimulation by bacterial lipopolysaccharide (LPS) (107). Hence, DUOX1 appears to be involved in other aspects of innate host defense in addition to direct microbial killing, and participates in epithelial signaling pathways that result in increased production of various epithelial mediators.…”

“…4) (158,159). Indeed, a number of downstream effects of P2 receptor activation, such as expression of MUC5AC, MMP-9 or IL-8 and stimulated cell migration, have been linked to activation of DUOX1 (87,105,107,108), suggesting a common association of DUOX with epithelial purinergic signaling. Intriguingly, NOX activation has similarly been associated with ATP-mediated purinergic signaling in several other mammalian cell types (160)(161)(162)(163)(164), and in NADPH oxidase-mediated wound responses in plants (165,166), which suggests that the general signaling pathway illustrated in Fig.…”

TACE/TGF- /EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components

“…Maximal CXCL8 responses further require a combined activation of the three major mitogen-activated protein kinase (MAPK) cascades: extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 [13,14]. A range of studies also suggests the involvement of the epidermal growth factor receptor (EGFR) in CXCL8 responses induced by different agents [15][16][17][18][19][20][21], and EGFR and CXCL8 expression correlate in the airway epithelium of patients with CF and severe asthma [22,23]. Accordingly, EGFR signalling has been suggested as a convergent pathway for regulation of CXCL8 and other immune responses [23].…”

“…Accordingly, EGFR signalling has been suggested as a convergent pathway for regulation of CXCL8 and other immune responses [23]. Recent studies with endogenous and microbial ligands have shown that CXCL8 regulation by EGFR involves transforming growth factor (TGF)-a ectodomain shedding by the metalloprotease tumour necrosis factor-a-converting enzyme (TACE)/ADAM-17 [20,21,24,25]. Whether organic or inorganic PM components regulate CXCL8 through similar mechanisms remains to be elucidated.…”