Skip to main content
SpringerLink
Log in

NF-κB and Mucosal Homeostasis

  • Chapter
  • First Online:
NF-kB in Health and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 349))

Abstract

NF-κB is well characterized as a primary mediator of inflammatory responses during infection and immune reactions, but it has recently become evident that NF-κB also mediates a potent cytoprotective, homeostatic function under basal conditions. This role is especially evident in the mammalian intestine, which is challenged not only with a range of microbial pathogens, but is also in constant contact with potent proinflammatory commensal bacteria and their products. Present data lead to the overall conclusion that antiapoptotic actions of NF-κB in intestinal epithelial cells dominate tissue responses to many acute inflammatory and injurious challenges, whereas proinflammatory and cell survival functions of NF-κB in macrophages and T cells govern chronic intestinal inflammation. This review focuses on the protective and homeostatic functions of NF-κB, and the importance of NF-κB in determining host–microbe interactions in the intestinal tract.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

DSS:

Dextran sulfate sodium

IKK:

IκB kinase

IBD:

Inflammatory bowel disease

JNK:

Jun N-terminal kinase

MAMP:

Microbial-associated molecular pattern

NF-κB:

Nuclear factor-κB

NLR:

NOD-like receptor

PRR:

Pattern recognition receptors

TLR:

Toll-like receptor

References

  • Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174:4453–4460

    PubMed  CAS  Google Scholar 

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  PubMed  CAS  Google Scholar 

  • Andoh A, Zhang Z, Inatomi O, et al (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129:969–984

    Article  PubMed  CAS  Google Scholar 

  • Angot A, Vergunst A, Genin S, Peeters N (2007) Exploitation of eukaryotic ubiquitin signaling pathways by effectors translocated by bacterial type III and type IV secretion systems. PLoS Pathog 3:e3

    Article  PubMed  Google Scholar 

  • Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ (2007) An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol 8:47–56

    Article  PubMed  CAS  Google Scholar 

  • Buchon N, Broderick NA, Chakrabarti S, Lemaitre B (2009) Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev 23:2333–2344

    Article  PubMed  CAS  Google Scholar 

  • Burdelya LG, Krivokrysenko VI, Tallant TC et al (2008) An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320:226–230

    Article  PubMed  CAS  Google Scholar 

  • Cario E, Gerken G, Podolsky DK (2007) Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359–1374

    Article  PubMed  CAS  Google Scholar 

  • Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313:1126–1130

    Article  PubMed  CAS  Google Scholar 

  • Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M (2003) The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 9:575–581

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi P, Pani G, Giannoni E et al (2003) Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161:933–944

    Article  PubMed  CAS  Google Scholar 

  • Collier-Hyams LS, Sloane V, Batten BC, Neish AS (2005) Cutting edge: bacterial modulation of epithelial signaling via changes in neddylation of cullin-1. J Immunol 175:4194–4198

    PubMed  CAS  Google Scholar 

  • Collier-Hyams LS, Zeng H, Sun J, Tomlinson AD, Bao ZQ, Chen H, Madara JL, Orth K, Neish AS (2002) Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappa B pathway. J Immunol 169:2846–2850

    PubMed  CAS  Google Scholar 

  • Costello CM, Mah N, Hasler R et al (2005) Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays. PLoS Med 2:e199

    Article  PubMed  Google Scholar 

  • Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638

    Article  PubMed  Google Scholar 

  • Eckmann L, Nebelsiek T, Fingerle AA et al (2008) Opposing functions of IKKbeta during acute and chronic intestinal inflammation. Proc Natl Acad Sci USA 105:15058–15063

    Article  PubMed  CAS  Google Scholar 

  • Egan LJ, Eckmann L, Greten FR, Chae S, Li ZW, Myhre GM, Robine S, Karin M, Kagnoff MF (2004) IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Natl Acad Sci USA 101:2452–2457

    Article  PubMed  CAS  Google Scholar 

  • Ferencz A, Racz B, Gasz B, Kalmar-Nagy K, Horvath OP, Roth E (2006) Threshold level of NF-kB activation in small bowel ischemic preconditioning procedure. Transplant Proc 38:1800–1802

    Article  PubMed  CAS  Google Scholar 

  • Galan JE (2009) Common themes in the design and function of bacterial effectors. Cell Host Microbe 5:571–579

    Article  PubMed  CAS  Google Scholar 

  • Greten FR, Arkan MC, Bollrath J et al (2007) NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130:918–931

    Article  PubMed  CAS  Google Scholar 

  • Hooper LV, Gordon JI (2001) Commensal host-bacterial relationships in the gut. Science 292:1115–1118

    Article  PubMed  CAS  Google Scholar 

  • Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S (2008) Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 3:352–363

    Article  PubMed  CAS  Google Scholar 

  • Iyer C, Kosters A, Sethi G, Kunnumakkara AB, Aggarwal BB, Versalovic J (2008) Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-kappaB and MAPK signalling. Cell Microbiol 10:1442–1452

    Article  PubMed  CAS  Google Scholar 

  • Jones RM, Wu H, Wentworth C, Luo L, Collier-Hyams L, Neish AS (2008) Salmonella AvrA coordinates suppression of host immune and apoptotic defenses via JNK pathway blockade. Cell Host Microbe 3:233–244

    Article  PubMed  CAS  Google Scholar 

  • Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663

    Article  PubMed  CAS  Google Scholar 

  • Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, Raz E (2005) Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 115:695–702

    PubMed  CAS  Google Scholar 

  • Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, Pettersson S, Conway S (2004) Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 5:104–112

    Article  PubMed  CAS  Google Scholar 

  • Kelly D, Conway S, Aminov R (2005) Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26:326–333

    Article  PubMed  CAS  Google Scholar 

  • Kim DW, Lenzen G, Page AL, Legrain P, Sansonetti PJ, Parsot C (2005) The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc Natl Acad Sci USA 102:14046–14051

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Wu H, Collier-Hyams LS, Hansen JM, Li T, Yamoah K, Pan ZQ, Jones DP, Neish AS (2007) Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. Embo J 26:4457–4466

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Wu H, Collier-Hyams LS, Kwon YM, Hanson JM, Neish AS (2009) The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation. J Immunol 182:538–546

    PubMed  CAS  Google Scholar 

  • Le Negrate G, Faustin B, Welsh K et al (2008) Salmonella secreted factor L deubiquitinase of Salmonella typhimurium inhibits NF-kappaB, suppresses IkappaBalpha ubiquitination and modulates innate immune responses. J Immunol 180:5045–5056

    PubMed  CAS  Google Scholar 

  • Lee WJ (2008) Bacterial-modulated signaling pathways in gut homeostasis. Sci Signal 1:pe24

    Google Scholar 

  • Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–848

    Article  PubMed  CAS  Google Scholar 

  • Lin PW, Myers LE, Ray L et al (2009) Lactobacillus rhamnosus blocks inflammatory signaling in vivo via reactive oxygen species generation. Free Radic Biol Med 47:1205–1211

    Article  PubMed  CAS  Google Scholar 

  • Madsen KL, Doyle JS, Jewell LD, Tavernini MM, Fedorak RN (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116:1107–1114

    Article  PubMed  CAS  Google Scholar 

  • McVay LD, Keilbaugh SA, Wong TM et al (2006) Absence of bacterially induced RELMbeta reduces injury in the dextran sodium sulfate model of colitis. J Clin Invest 116:2914–2923

    Article  PubMed  CAS  Google Scholar 

  • Menard S, Candalh C, Bambou JC, Terpend K, Cerf-Bensussan N, Heyman M (2004) Lactic acid bacteria secrete metabolites retaining anti-inflammatory properties after intestinal transport. Gut 53:821–828

    Article  PubMed  CAS  Google Scholar 

  • Moore-Olufemi SD, Kozar RA, Moore FA, Sato N, Hassoun HT, Cox CS Jr, Kone BC (2005) Ischemic preconditioning protects against gut dysfunction and mucosal injury after ischemia/reperfusion injury. Shock 23:258–263

    PubMed  Google Scholar 

  • Mukherjee S, Hao YH, Orth K (2007) A newly discovered post-translational modification—the acetylation of serine and threonine residues. Trends Biochem Sci 32:210–216

    Article  PubMed  CAS  Google Scholar 

  • Neish AS (2009) Microbes in gastrointestinal health and disease. Gastroenterology 136:65–80

    Article  PubMed  Google Scholar 

  • Neish AS, Gewirtz AT, Zeng H, Young AN, Hobert ME, Karmali V, Rao AS, Madara JL (2000) Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination. Science 289:1560–1563

    Article  PubMed  CAS  Google Scholar 

  • Nenci A, Becker C, Wullaert A et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–561

    Article  PubMed  CAS  Google Scholar 

  • Neurath MF, Pettersson S, Meyer zum Buschenfelde KH, Strober W (1996) Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2:998–1004

    Article  PubMed  CAS  Google Scholar 

  • Ogier-Denis E, Mkaddem SB, Vandewalle A (2008) NOX enzymes and toll-like receptor signaling. Semin Immunopathol 30:291–300

    Article  PubMed  CAS  Google Scholar 

  • Orth K, Palmer LE, Bao ZQ, Stewart S, Rudolph AE, Bliska JB, Dixon JE (1999) Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285:1920–1923

    Article  PubMed  CAS  Google Scholar 

  • Pena JA, Versalovic J (2003) Lactobacillus rhamnosus GG decreases TNF-alpha production in lipopolysaccharide-activated murine macrophages by a contact-independent mechanism. Cell Microbiol 5:277–285

    Article  PubMed  CAS  Google Scholar 

  • Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y, De Simone C, Chang EB (2004) Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 127:1474–1487

    Article  PubMed  CAS  Google Scholar 

  • Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS (2005) Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA 102:99–104

    Article  PubMed  CAS  Google Scholar 

  • Rafiee P, Stein DJ, Nelson VM, Otterson MF, Shaker R, Binion DG (2010) Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC). Am J Physiol Gastrointest Liver Physiol 298:G167–G176

    Article  PubMed  CAS  Google Scholar 

  • Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241

    Article  PubMed  CAS  Google Scholar 

  • Rogler G, Brand K, Vogl D et al (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369

    Article  PubMed  CAS  Google Scholar 

  • Rytkonen A, Holden DW (2007) Bacterial interference of ubiquitination and deubiquitination. Cell Host Microbe 1:13–22

    Article  PubMed  CAS  Google Scholar 

  • Sansonetti PJ (2004) War and peace at mucosal surfaces. Nat Rev Immunol 4:953–964

    Article  PubMed  CAS  Google Scholar 

  • Sartor RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134:577–594

    Article  PubMed  CAS  Google Scholar 

  • Schreiber S, Nikolaus S, Hampe J (1998) Activation of nuclear factor kappa B inflammatory bowel disease. Gut 42:477–484

    Article  PubMed  CAS  Google Scholar 

  • Steinbrecher KA, Harmel-Laws E, Sitcheran R, Baldwin AS (2008) Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation. J Immunol 180:2588–2599

    PubMed  CAS  Google Scholar 

  • Suzuki T, Yamashita K, Jomen W et al (2008) The novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin, prevents local and remote organ injury following intestinal ischemia/reperfusion in rats. J Surg Res 149:69–75

    Article  PubMed  CAS  Google Scholar 

  • Terada LS (2006) Specificity in reactive oxidant signaling: think globally, act locally. J Cell Biol 174:615–623

    Article  PubMed  CAS  Google Scholar 

  • Tien MT, Girardin SE, Regnault B, Le Bourhis L, Dillies MA, Coppee JY, Bourdet-Sicard R, Sansonetti PJ, Pedron T (2006) Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells. J Immunol 176:1228–1237

    PubMed  CAS  Google Scholar 

  • Vijay-Kumar M, Aitken JD, Sanders CJ, Frias A, Sloane VM, Xu J, Neish AS, Rojas M, Gewirtz AT (2008) Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. J Immunol 180:8280–8285

    PubMed  CAS  Google Scholar 

  • Vijay-Kumar M, Sanders CJ, Taylor RT et al (2007) Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest 117:3909–3921

    PubMed  CAS  Google Scholar 

  • Vijay-Kumar M, Wu H, Jones R, Grant G, Babbin B, King TP, Kelly D, Gewirtz AT, Neish AS (2006) Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. Am J Pathol 169:1686–1700

    Article  PubMed  CAS  Google Scholar 

  • Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB (2007) Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132:562–575

    Article  PubMed  CAS  Google Scholar 

  • Zaph C, Troy AE, Taylor BC et al (2007) Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446:552–556

    Article  PubMed  CAS  Google Scholar 

  • Zeng H, Carlson AQ, Guo Y, Yu Y, Collier-Hyams LS, Madara JL, Gewirtz AT, Neish AS (2003) Flagellin is the major proinflammatory determinant of enteropathogenic Salmonella. J Immunol 171:3668–3674

    PubMed  CAS  Google Scholar 

  • Zeng H, Wu H, Sloane V, Jones R, Yu Y, Lin P, Gewirtz AT, Neish AS (2006) Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am J Physiol Gastrointest Liver Physiol 290:G96–G108

    Article  PubMed  CAS  Google Scholar 

  • Zou L, Attuwaybi B, Kone BC (2003) Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 284:G713–G721

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0063, USA

    Lars Eckmann

  2. Department of Pathology and Laboratory Medicine, Emory University, 615 Michaels St, Atlanta, GA, 30322, USA

    Andrew S. Neish

Authors
  1. Lars Eckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew S. Neish
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lars Eckmann or Andrew S. Neish .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Pharmacology, University of California, San Diego, Gilman Dr. 9500, La Jolla, 92093-0636, California, USA

    Michael Karin

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Eckmann, L., Neish, A.S. (2010). NF-κB and Mucosal Homeostasis. In: Karin, M. (eds) NF-kB in Health and Disease. Current Topics in Microbiology and Immunology, vol 349. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_103

Download citation

Publish with us

Policies and ethics

Search

Navigation