title: Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells.
abstract: Chronic interstitial lung disease in both adults and children is associated with mutations of the surfactant protein C (SP-C) proprotein. Among these, mutations within the distal COOH propeptide, known as the BRICHOS domain, are associated with a severe disease phenotype. We showed that prolonged expression of the BRICHOS mutants, SP-C(Δexon4) and SP-C(L188Q), destabilizes endoplasmic reticulum (ER) quality-control mechanisms (the unfolded protein response, or UPR), resulting in the induction of ER stress signaling, an inhibition of the ubiquitin/proteasome system, and the activation of apoptotic pathways. Based on recent observations that the UPR and ER stress can be linked to the induction of proinflammatory signaling, we hypothesized that the epithelial cell dysfunction mediated by SP-C BRICHOS mutants would activate proinflammatory signaling pathways. In a test of this hypothesis, A549 and human embryonic kidney epithelial (HEK293) cells, transiently transfected with either SP-C(Δexon4) or SP-C(L188Q) mutants, each promoted the upregulation of multiple UPR response genes, including homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) and GRP78. Commensurate with these results, increases in IL-8 secretion occurred and were accompanied by the activation of c-Jun N-terminal kinase (JNK)/activating protein-1 signaling. The stimulation of IL-8 cytokine release was completely attenuated by treatment with the JNK-specific inhibitor, SP600125. In addition, SP-C(Δexon4), but not SP-C(L188Q), activated NFκB. The treatment of SP-C(Δexon4) transfected cells with 4-phenylbutyric acid, a small molecule chaperone known to improve protein folding, blocked the activation of NFκB, but not the release of IL-8. Taken together, the results support the role of JNK signaling in mediating SP-C BRICHOS-induced cytokine release, and provide a link between SP-C BRICHOS mutants and proinflammatory cytokine signaling.
authors.affiliation: Surfactant Biology Laboratories, Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: Jean Ann
authors.initials: JA
authors.lastname: Maguire
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C485932:HERPUD1 protein, human; C000717247:HSPA5 protein, human; D016209:Interleukin-8; D008565:Membrane Proteins; D016328:NF-kappa B; D037721:Pulmonary Surfactant-Associated Protein C
references.citation: J Biol Chem. 2005 Nov 25;280(47):39002-15
references.pmid: 16183649
references.citation: EMBO J. 1996 Jun 3;15(11):2760-70
references.pmid: 8654373
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):732-7
references.pmid: 14644198
references.citation: Int J Biochem Cell Biol. 2008;40(12):2702-6
references.pmid: 18678273
references.citation: Am J Pathol. 2009 Jul;175(1):3-16
references.pmid: 19497999
references.citation: Biol Chem. 2002 Feb;383(2):271-82
references.pmid: 11934265
references.citation: Annu Rev Physiol. 2005;67:663-96
references.pmid: 15709974
references.citation: Allergy Asthma Proc. 2002 Jan-Feb;23(1):19-25
references.pmid: 11894730
references.citation: Clin Med (Lond). 2007 Oct;7(5):446-7
references.pmid: 17990707
references.citation: Respir Res. 2002;3:14
references.pmid: 11806849
references.citation: J Biol Chem. 2002 May 31;277(22):19929-37
references.pmid: 11907042
references.citation: J Immunol. 1997 Aug 1;159(3):1437-43
references.pmid: 9233641
references.citation: Br J Pharmacol. 2007 Apr;150(7):829-31
references.pmid: 17325655
references.citation: Chest. 2002 Mar;121(3 Suppl):20S-21S
references.pmid: 11893657
references.citation: Trends Biochem Sci. 2002 Jul;27(7):329-32
references.pmid: 12114016
references.citation: Annu Rev Immunol. 1994;12:141-79
references.pmid: 8011280
references.citation: Science. 2003 Oct 31;302(5646):819-22
references.pmid: 14593166
references.citation: J Proteome Res. 2006 Mar;5(3):562-71
references.pmid: 16512671
references.citation: Am J Respir Cell Mol Biol. 1999 Oct;21(4):455-62
references.pmid: 10502555
references.citation: Nature. 2008 Jul 24;454(7203):455-62
references.pmid: 18650916
references.citation: Science. 2000 Jan 28;287(5453):664-6
references.pmid: 10650002
references.citation: Am J Respir Crit Care Med. 2008 Oct 15;178(8):838-46
references.pmid: 18635891
references.citation: Am J Respir Cell Mol Biol. 2005 Jun;32(6):521-30
references.pmid: 15778495
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Nucleic Acids Res. 2006 Jun 06;34(10):3116-27
references.pmid: 16757577
references.citation: Am J Physiol Cell Physiol. 2007 Jul;293(1):C411-8
references.pmid: 17475668
references.citation: Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64
references.pmid: 10673212
references.citation: Science. 2006 Aug 25;313(5790):1137-40
references.pmid: 16931765
references.citation: Cancer Treat Rev. 2006 May;32(3):157-65
references.pmid: 16516391
references.citation: J Biol Chem. 2003 Dec 26;278(52):52739-46
references.pmid: 14525980
references.citation: EMBO J. 1995 Jun 1;14(11):2580-8
references.pmid: 7781611
references.citation: Nat Med. 2004 Jan;10(1):98-102
references.pmid: 14702639
references.citation: J Clin Invest. 1997 Nov 15;100(10):2457-65
references.pmid: 9366560
references.citation: J Cell Biol. 2006 Jan 30;172(3):395-407
references.pmid: 16449190
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L720-9
references.pmid: 17586700
references.citation: Trends Mol Med. 2001 Nov;7(11):479-82
references.pmid: 11689312
references.citation: Eur Respir J. 2002 May;19(5):794-6
references.pmid: 12030715
references.citation: Int J Biochem Cell Biol. 2008;40(9):1703-15
references.pmid: 18434235
references.citation: Am J Physiol. 1999 Nov;277(5):L1034-44
references.pmid: 10564190
references.citation: J Pharmacol Exp Ther. 2008 Sep;326(3):949-56
references.pmid: 18574003
references.citation: Mol Pharmacol. 2008 Nov;74(5):1359-66
references.pmid: 18669446
references.citation: Cell. 2000 Oct 13;103(2):239-52
references.pmid: 11057897
references.citation: Nat Rev Immunol. 2002 Oct;2(10):725-34
references.pmid: 12360211
references.citation: N Engl J Med. 2001 Feb 22;344(8):573-9
references.pmid: 11207353
references.citation: Cell Immunol. 2002 Jul-Aug;218(1-2):26-33
references.pmid: 12470611
references.citation: J Cell Sci. 2003 Feb 15;116(Pt 4):683-92
references.pmid: 12538769
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1119-26
references.pmid: 18390830