Interleukin-1 receptor associated kinase regulates lipopolysaccharide-induced airway mucus hypersecretion through a TLR-4/MyD88 related pathway_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

HE Mingxin ^1,2 , ZHANG Hua ² , ZHOU Xiangdong ^1,2 , Juliy M Perelman ³ , Victor P Kolosov ³ ,  LI Qi ^1,2

1. Department of Emergency Medicine, First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P. R. China;
2. Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan 571199, P. R. China;
3. Far Eastern Scientific Center of Physiology and Pathology of Respiration, Blagoveschensk 675000, Russia;

Corresponding author：

LI Qi, Email: lqlq2198210@sina.com

Keywords：

Interleukin-1 receptor associated kinase; lipopolysaccharide; airway mucus hypersecretion

DOI：

10.7507/1671-6205.202002114

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Objective To investigate whether interleukin-1 receptor associated kinase (IRAK) participates the airway mucus hypersecretion induced by lipopolysaccharide (LPS). Methods The expression of Toll-like receptor (TLR)-4 or IRAK was down regulated by the transfection of specific small interfering RNA (siRNA). The transcription level of mucin 5AC (MUC5AC) mRNA as well as the secretion level of MUC5AC protein were judged by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. The activity of signaling molecules involved in TLR-4 associated pathway, such as the phosphorylated IRAK, nuclear translocation of NF-κB p65, was analyzed by Western blot. Results The level of intracellular phosphorylated IRAK was increased by stimulation of LPS in BEAS-2B cells. However, down-regulation of TLR-4 by siRNA could partially attenuate the additional phosphorylation of IRAK induced by LPS (P<0.05). LPS elicited a nuclear translocation of NF-κB p65 in BEAS-2B cells, which could be partially blocked by the down-regulation of TLR-4 or IRAK. With RT-PCR, an increased expression level of MUC5AC mRNA was discovered in wild-type BEAS-2B cells (0.82±0.09) than TLR-4 defect cells (0.36±0.05), IRAK defect cells (0.48±0.05) and IRAK inhibitor pretreated cells (0.57±0.07) (all P<0.05). Meanwhile, according to ELISA, an increased secretion level of MUC5AC protein was recorded in wild-type BEAS-2B cells [(0.76±0.09) μg/L] than TLR-4 defect cells [(0.33±0.04) μg/L], IRAK defect cells [(0.42±0.05) μg/L] and IRAK inhibitor pretreated cells [(0.51±0.06) μg/L] (all P<0.05). Conclusion As an crucial regulator of TLR dependent signaling pathway, IRAK may participate the airway mucus over-synthesis induced by LPS.

Citation： HE Mingxin, ZHANG Hua, ZHOU Xiangdong, Juliy M Perelman, Victor P Kolosov, LI Qi. Interleukin-1 receptor associated kinase regulates lipopolysaccharide-induced airway mucus hypersecretion through a TLR-4/MyD88 related pathway. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(1): 50-54. doi: 10.7507/1671-6205.202002114 Copy

1.	Voynow JA, Rubin BK. Mucins, mucus, and sputum. Chest, 2009, 135(2): 505-512.
2.	Rubin BK. Physiology of airway mucus clearance. Respir Care, 2002, 47(7): 761-768.
3.	刘峰, 周向东, 余红梅, 等. Elafin对气道上皮细胞黏蛋白5AC的调节作用. 中国呼吸与危重症监护杂志, 2018, 17(3): 296-300.
4.	Chen L, Wang T, Zhang JY, et al. Toll-like receptor 4 relates to lipopolysaccharide-induced mucus hypersecretion in rat airway. Arch Med Res, 2009, 40(1): 10-17.
5.	金生, 张大志, 陈压西, 等. Toll样受体研究进展与临床免疫. 重庆医学, 2004, 33(9): 1423-1426.
6.	Roger T, Froidevaux C, Le Roy D, et al. Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A, 2009, 106(7): 2348-2352.
7.	Miyata M, Lee JY, Susuki-Miyata S, et al. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-MM. Nat Commun, 2015, 6: 6062.
8.	Ringwood L, Li LW. The involvement of the interleukin-1 receptor-associated kinases (IRAKs) in cellular signaling networks controlling inflammation. Cytokine, 2008, 42(1): 1-7.
9.	Heinz LX, Rebsamen M, Rossi DC, et al. The death domain-containing protein Unc5 CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. Cell Death Differ, 2012, 19(4): 722-731.
10.	Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol, 2003, 3(2): 169-176.
11.	Daigneault J, Klemetsaune L, Wasserman SA. The IRAK homolog pelle is the functional counterpart of IκB kinase in the drosophila toll pathway. PLoS One, 2013, 8(9): e75150.
12.	Potnis PA, Dutta DK, Wood SC. Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles. Cell Immunol, 2013, 282(1): 53-65.

1. Voynow JA, Rubin BK. Mucins, mucus, and sputum. Chest, 2009, 135(2): 505-512.
2. Rubin BK. Physiology of airway mucus clearance. Respir Care, 2002, 47(7): 761-768.
3. 刘峰, 周向东, 余红梅, 等. Elafin对气道上皮细胞黏蛋白5AC的调节作用. 中国呼吸与危重症监护杂志, 2018, 17(3): 296-300.
4. Chen L, Wang T, Zhang JY, et al. Toll-like receptor 4 relates to lipopolysaccharide-induced mucus hypersecretion in rat airway. Arch Med Res, 2009, 40(1): 10-17.
5. 金生, 张大志, 陈压西, 等. Toll样受体研究进展与临床免疫. 重庆医学, 2004, 33(9): 1423-1426.
6. Roger T, Froidevaux C, Le Roy D, et al. Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A, 2009, 106(7): 2348-2352.
7. Miyata M, Lee JY, Susuki-Miyata S, et al. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-MM. Nat Commun, 2015, 6: 6062.
8. Ringwood L, Li LW. The involvement of the interleukin-1 receptor-associated kinases (IRAKs) in cellular signaling networks controlling inflammation. Cytokine, 2008, 42(1): 1-7.
9. Heinz LX, Rebsamen M, Rossi DC, et al. The death domain-containing protein Unc5 CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. Cell Death Differ, 2012, 19(4): 722-731.
10. Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol, 2003, 3(2): 169-176.
11. Daigneault J, Klemetsaune L, Wasserman SA. The IRAK homolog pelle is the functional counterpart of IκB kinase in the drosophila toll pathway. PLoS One, 2013, 8(9): e75150.
12. Potnis PA, Dutta DK, Wood SC. Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles. Cell Immunol, 2013, 282(1): 53-65.

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Interleukin-1 receptor associated kinase regulates lipopolysaccharide-induced airway mucus hypersecretion through a TLR-4/MyD88 related pathway

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