Home LiteratureArticle Details
PMID: 9541482 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.

The Journal of clinical investigation ·Vol. 101 ·No. 8 ·1998-04-15 ·Pages 1547-50

Castagliuolo I, Riegler M, Pasha A, Nikulasson S, Lu B, Gerard C, Gerard NP, Pothoulakis C

Abstract

Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.

MeSH Terms
Animals Bacterial Toxins/toxicity Clostridioides difficile/pathogenicity Enterocolitis, Pseudomembranous/etiology,metabolism,pathology Enterotoxins/toxicity Humans Ileum/drug effects,metabolism,pathology In Vitro Techniques Mice Mice, Knockout RNA, Messenger/genetics,metabolism Receptors, Neurokinin-1/deficiency,genetics,metabolism Substance P/metabolism Tumor Necrosis Factor-alpha/genetics,metabolism
Chemicals
Bacterial Toxins Enterotoxins RNA, Messenger Receptors, Neurokinin-1 Tumor Necrosis Factor-alpha tcdA protein, Clostridium difficile Substance P
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Castagliuolo I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Riegler M
Pasha A
Nikulasson S
Lu B
Gerard C
Gerard N P
Pothoulakis C
References (26)
26 references, click to expand
  1. Amino-acid sequence of substance P.
    Nat New Biol. 1971 Jul 21;232(29):86-7 PMID: 5285346
  2. IL-11 inhibits Clostridium difficile toxin A enterotoxicity in rat ileum.
    Am J Physiol. 1997 Aug;273(2 Pt 1):G333-41 PMID: 9277411
  3. Mast cell heterogeneity: effects of neuroenteric peptides on histamine release.
    J Immunol. 1985 Aug;135(2):1331-7 PMID: 2409146
  4. Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.
    Proc Natl Acad Sci U S A. 1988 May;85(9):3235-9 PMID: 2834738
  5. Effect of neuropeptides on production of inflammatory cytokines by human monocytes.
    Science. 1988 Sep 2;241(4870):1218-21 PMID: 2457950
  6. Gastrointestinal tachykinin receptors.
    Life Sci. 1988;43(26):2203-8 PMID: 2850429
  7. Characterization of rabbit ileal receptors for Clostridium difficile toxin A. Evidence for a receptor-coupled G protein.
    J Clin Invest. 1991 Jul;88(1):119-25 PMID: 1905325
  8. Segmental heterogeneity of the rat colon in the response to activators of secretion on the cAMP-, the cGMP- and the Ca(2+)-pathway.
    Acta Physiol Scand. 1991 Jul;142(3):375-86 PMID: 1656704
  9. Effects of tachykinins on myenteric neurones of the guinea-pig gastric corpus: involvement of NK-3 receptors.
    Pflugers Arch. 1991 Dec;419(6):566-71 PMID: 1724075
  10. Modulation of the mRNAs encoding substance P and its receptor in rat macrophages by LPS.
    Reg Immunol. 1992 Mar-Apr;4(2):105-12 PMID: 1380279
  11. Analysis of a nonpeptide antagonist for substance P on myenteric neurons of guinea-pig small intestine.
    Eur J Pharmacol. 1993 Mar 2;232(2-3):235-9 PMID: 7682179
  12. Clostridium difficile colitis.
    N Engl J Med. 1994 Jan 27;330(4):257-62 PMID: 8043060
  13. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin.
    Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):947-51 PMID: 7508124
  14. Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit.
    J Clin Invest. 1994 Mar;93(3):1257-65 PMID: 7907603
  15. Beneficial effects of local or systemic lidocaine in experimental colitis.
    Am J Physiol. 1994 Apr;266(4 Pt 1):G560-7 PMID: 8178994
  16. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum.
    Gastroenterology. 1994 Sep;107(3):657-65 PMID: 7915699
  17. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro.
    J Clin Invest. 1995 May;95(5):2004-11 PMID: 7738167
  18. Substance P induces ion secretion in mouse small intestine through effects on enteric nerves and mast cells.
    Am J Physiol. 1995 Jul;269(1 Pt 1):G85-92 PMID: 7543249
  19. Increased substance P receptor expression by blood vessels and lymphoid aggregates in Clostridium difficile-induced pseudomembranous colitis.
    Dig Dis Sci. 1996 Mar;41(3):614-20 PMID: 8617145
  20. Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment.
    Gut. 1996 Mar;38(3):337-47 PMID: 8675084
  21. Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A.
    J Clin Invest. 1996 Aug 1;98(3):641-9 PMID: 8698855
  22. Neurogenic amplification of immune complex inflammation.
    Science. 1996 Sep 20;273(5282):1722-5 PMID: 8781237
  23. Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum.
    Gastroenterology. 1996 Nov;111(5):1272-80 PMID: 8898641
  24. Large clostridial cytotoxins--a family of glycosyltransferases modifying small GTP-binding proteins.
    Trends Microbiol. 1996 Oct;4(10):375-82 PMID: 8899962
  25. Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4788-93 PMID: 9114070
  26. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker.
    J Invest Dermatol. 1982 Mar;78(3):206-9 PMID: 6276474
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI2039
Published
1998-04-15
Pages
1547-50
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC508733
Subset
IM
Grants
NIDDK NIH HHS · DK-47343 · United States
NHLBI NIH HHS · HL-36162 · United States
NHLBI NIH HHS · HL-51366 · United States
External Links
PubMed source DOI: 10.1172/JCI2039 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2