Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections

Jae Hyang Lim, Brigid Stirling, Jonathan Derry, Tomoaki Koga, Hirofumi Jono, Chang Hoon Woo, Haodong Xu, Patricia Bourne, Un Hwan Ha, Hajime Ishinaga, Haidong Xu, Ali Andalibi, Xin Hua Feng, Hongguang Zhu, Yuxian Huang, Wenhong Zhang, Xinhua Weng, Chen Yan, Zhinan Yin, David E. BrilesRoger J. Davis, Richard A. Flavell, Jian Dong Li

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

Streptococcus pneumoniae (S. pneumoniae) causes high early mortality in pneumococcal pneumonia, which is characterized by acute lung injury (ALI). The molecular mechanisms underlying ALI and the high early mortality remain unknown. Despite recent studies that identify deubiquitinating enzyme cylindromatosis (CYLD) as a key regulator for T cell development, tumor cell proliferation, and NF-κB transcription factor signaling, its role in regulating bacteria-induced lethality, however, is unknown. Here, we showed that CYLD deficiency protected mice from S. pneumoniae pneumolysin (PLY)-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia.

Original languageEnglish
Pages (from-to)349-360
Number of pages12
JournalImmunity
Volume27
Issue number2
DOIs
StatePublished - 24 Aug 2007

Bibliographical note

Funding Information:
We are grateful to Drs. R. Malley and A. Srivastava for kindly providing the purified native PLY and Dr. G. Mosialos for kindly providing anti-CYLD antibody. We also thank Drs. R. Bernards and J. Han for kindly providing various expression plasmids. Out thanks also extend to Dr. R. Malley for his helpful input and discussions regarding the manuscript and Dr. G. Mosialos for critically reviewing this manuscript. This work was supported in part by grants from National Institute of Health DC005843 and DC004562 and a start-up fund from University of Rochester Medical Center (to J.-D.L.), Major State Basic Research (973) Program (2005CB523102), China (to W.Z. and X.W.), Arthritis Foundation Investigator Award, National Institute of Arthritis and Musculoskeltal and Skin Disease Grant KO1 AR 02188, National Institute of Health Grants RO1AI56219 (to Z.Y.), HL077789 and AHA EIA0740021 (to C.Y.) and by Amgen. RJD and RAF are investigators of the Howard Hughes Medical Institute. We declare that a patent on using recombinant PAI-1 for the treatment of lethal bacterial infections has been filed by University of Rochester.

Keywords

  • CELLIMMUNO
  • HUMDISEASE
  • MICROBIO

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