Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Abstract

MUC1 (or Muc1 in nonhuman species) is a membrane-tethered mucin expressed on the apical surface of mucosal epithelia (including those of the airways) that suppresses Toll-like receptor (TLR) signaling. We sought to determine whether the anti-inflammatory effect of MUC1 is operative during infection with nontypeable Haemophilus influenzae (NTHi), and if so, which TLR pathway was affected. Our results showed that: (1) a lysate of NTHi increased the early release of IL-8 and later production of MUC1 protein by A549 cells in dose-dependent and time-dependent manners, compared with vehicle control; (2) both effects were attenuated after transfection of the cells with a TLR2-targeting small interfering (si) RNA, compared with a control siRNA; (3) the NTHi-induced release of IL-8 was suppressed by an overexpression of MUC1, and was enhanced by the knockdown of MUC1; (4) the TNF-a released after treatment with NTHi was sufficient to up-regulate MUC1, which was completely inhibited by pretreatment with a soluble TNF-a receptor; and (5) primary murine tracheal surface epithelial (MTSE) cells from Muc1 knockout mice exhibited an increased in vitro production of NTHi-stimulated keratinocyte chemoattractant compared with MTSE cells from Muc1-expressing animals. These results suggest a hypothetical feedback loop model whereby NTHi activates TLRs (mainly TLR2) in airway epithelial cells, leading to the increased production of TNF-a and IL-8, which subsequently up-regulate the expression of MUC1, resulting in suppressed TLR signaling and decreased production of IL-8. This report is the first, to the best of our knowledge, demonstrating that the inflammatory response in airway epithelial cells during infection with NTHi is controlled by MUC1 mucin, mainly through the suppression of TLR2 signaling.

The cell surface mucin MUC1 limits the severity of influenza A virus infection

“…This results in inhibition of TLR signaling and a dampening of airway inflammation. This pathway has been elucidated in TLR5-dependent activation of primary epithelial cells in Pseudomonas aeruginosa infection, 14,15 but is also consistent with findings of negative regulation of other TLR molecules 12 and with the antiinflammatory effect of MUC1 during respiratory syncytial virus infection 13 and Haemophilus influenzae infection 44 of lung epithelial cells in vitro.…”

Mucin 1 is a novel glycoprotein involved in host defense against invasive pneumococcal disease

“…16,17 This is important because MUC1 has been shown to play a critical role in host defense, reducing the inflammatory response after infection of the respiratory tract by syncytial virus or non-typeable Haemophilus influenzae. 18,19 These results are consistent with the protective role of MUC1 against S. pneumoniae, as Muc1 ¡/¡ mice had significantly increased levels of pro-inflammatory cytokines in the lung compared with wild-type mice, confirming that MUC1 ameliorates the inflammatory response of the airway induced by pneumococcal infection. 13 Since mucin glycoproteins are one of the major constituents of epithelial cells lining the gastrointestinal tract with many cells expressing multiple members of this family, their protective role neutralizing the invading pathogen is critical to prevent the infection of this mucosal barrier by enteric pathogens.…”

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

“…AGS cells in 24-well plates were transfected with 20 pmoles/well of a MUC1-targeting small interfering RNA (siRNA) (sense, 5=-GUUCAGUGCCCAGCUCUACdTdT-3=; antisense, 5=-GUAGAGCUGGGCACUGAACdTdT-3=) or with a nontargeting control siRNA (sense, 5=-GCGCGCUUUGUAGGAUUCGdTdT-3=; antisense, 5=-CGAAUCCUACAAAGCGCGCdTdT-3=) (Dharmacon, Lafayette, CO), using 2.0 l/well of Lipofectamine (Invitrogen) as described (18). Prior studies have documented the specificity of the MUC1 siRNA with no demonstrable off-target effects (18,23,30,32,33,35).…”