CYLD Negatively Regulates Nontypeable Haemophilus influenzae-Induced IL-8 Expression via Phosphatase MKP-1-Dependent Inhibition of ERK

Abstract

Nontypeable Haemophilus influenzae (NTHi), a Gram-negative bacterium, is the primary cause of otitis media in children and the exacerbation of chronic obstructive pulmonary disease in adults. A hallmark of both diseases is an overactive inflammatory response, including the upregulation of chemokines, such as interleukin-8 (IL-8). An appropriate inflammatory response is essential for eradicating pathogens. However, excessive inflammation can cause host tissue damage. Therefore, expression of IL-8 must be tightly regulated. We previously reported that NTHi induces IL-8 expression in an ERK-dependent manner. We also have shown that the deubiquitinase cylindromatosis (CYLD) suppresses NTHi-induced inflammation. However, the underlying molecular mechanism of how CYLD negatively regulates ERK-mediated IL-8 production is largely unknown. Here, we examine both human lung epithelial A549 cells and lung of Cyld −/− mice to show that CYLD specifically targets the activation of ERK. Interestingly, CYLD enhances NTHi-induced upregulation of another negative regulator, MAP Kinase Phosphatase-1 (MKP-1), which, in turn, leads to reduced ERK activation and subsequent suppression of IL-8. Taken together, the CYLD suppression of ERK-dependent IL-8 via MKP-1 may bring novel insights into the tight regulation of inflammatory responses and also lead to innovative therapeutic strategies for controlling these responses by targeting key negative regulators of inflammation.

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

“…Glucocorticoids enhance NTHi-induced TLR2 upregulation via MKP1 phosphatase-dependent inhibition of p38 MAPK (21,24). MKP1 also seems to lead to reduced activation of the extracellular signal-regulated kinase (ERK) MAPK (39). Genome profiling revealed that the MKP1 encoding gene DUSP1 and p38 MAPK signaling are overexpressed in NTHi-infected cells.…”

Asian Sand Dust Particles Increased Pneumococcal Biofilm Formation in vitro and Colonization in Human Middle Ear Epithelial Cells and Rat Middle Ear Mucosa

“…The FBXO11 is another important OM-related gene in mouse model mutation in FBXO11 that caused OM (Hardisty-Hughes et al, 2006). The deubiquitinase cylindromatosis (CYLD) gene expression involved in the suppression of the H. influenzae induced expression of pro-inflammatory chemokines (Wang et al, 2014). It has been suggested that PM weakens the host innate defense and obstructs the antibacterial peptides and proteins such as secretory leukocyte protease inhibitor and defensins (Chen et al, 2010(Chen et al, , 2018.…”

CYLD: a critical regulator of hypoxia-mediated inflammation in tumors

“…A series of evidence suggests that loss of CYLD expression is deeply associated with a wide variety of diseases, including malignant tumors, inflammatory diseases, infectious diseases, lung fibrosis, neural development, and cardiovascular dysfunction [79][80][81][82][83][84][85] . In this review, we described the clinical significance of CYLD, particularly focusing on the roles of CYLD as a critical regulator of hypoxia-mediated inflammation in GBM, which may affect the long-term efficacy of anti-VEGF therapy.…”