CYLD negatively regulates nontypeable Haemophilus influenzae-induced IL-8 expression via phosphatase MKP-1-dependent inhibition of ERK.
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.
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Wenzhuo Y
WY
Wang
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
Kensei
K
Komatsu
Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, China; Department of Viral Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Yuxian
Y
Huang
Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, China.
Jing
J
Wu
Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, China.
Wenhong
W
Zhang
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
Ji-Yun
JY
Lee
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
Masanori
M
Miyata
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
Haidong
H
Xu
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
Jian-Dong
JD
Li
D000818:Animals; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006192:Haemophilus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006193:Haemophilus influenzae / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D016209:Interleukin-8; D025521:Tumor Suppressor Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C409984:CYLD protein, human; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases