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PMID: 9114070 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 9 ·1997-04-29 ·Pages 4788-93

Castagliuolo I, Keates AC, Qiu B, Kelly CP, Nikulasson S, Leeman SE, Pothoulakis C

Abstract

Previously we reported that pretreatment of rats with the substance P (SP) antagonist CP-96,345 inhibits the enterotoxic responses following administration of toxin A from Clostridium difficile into ileal loops, indicating that SP participates in the intestinal responses to this toxin. We now report that injection of toxin A into rat ileum causes a rapid increase in SP content in lumbar dorsal root ganglia (DRG) and mucosal scrapings 30-60 min after toxin A administration. Toxin A-mediated fluid secretion, mannitol permeability, and ileal histologic damage is significantly increased only after 2 hr. Toxin A also causes an increase in the abundance of SP mRNA in lumbar DRG and ileal mucosa as measured by reverse transcription-PCR. Lamina propria macrophages (LPMs) obtained from toxin A-injected loops release greater amounts of tumor necrosis factor alpha (TNFalpha) and SP as compared with LPMs isolated from buffer-injected loops (P < 0.01). Pretreatment of rats with the SP antagonist CP-96,345 inhibits toxin A-mediated TNFalpha release from isolated LPMs, whereas an inactive enantiomer (CP-96,344) of the SP antagonist has no effect. LPMs obtained from toxin A-injected ileal loops incubated in vitro with SP (10(-8) to 10(-9) M) show enhanced TNFalpha secretion, whereas LPMs isolated from buffer-injected loops do not respond to SP. In addition, LPMs obtained from toxin A-injected ileal loops incubated in vitro with CP-96,345 showed a diminished TNFalpha release. Our results indicate that activated LPMs secrete SP during toxin A enteritis that can lead to secretion of cytokines, suggesting an autocrine/paracrine regulation of cytokine secretion by SP from LPMs during intestinal inflammation.

MeSH Terms
Animals Bacterial Toxins/pharmacology Biphenyl Compounds/pharmacology Clostridioides difficile Enterotoxins/pharmacology Ganglia, Spinal/metabolism Ileitis/metabolism Intestinal Mucosa/metabolism Lumbosacral Region Macrophage Activation Macrophages/metabolism Male RNA, Messenger/analysis Rats Rats, Wistar Substance P/antagonists & inhibitors,biosynthesis,genetics Tumor Necrosis Factor-alpha/metabolism
Chemicals
Bacterial Toxins Biphenyl Compounds Enterotoxins RNA, Messenger Tumor Necrosis Factor-alpha tcdA protein, Clostridium difficile Substance P CP 96345
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Castagliuolo I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Keates A C
Qiu B
Kelly C P
Nikulasson S
Leeman S E
Pothoulakis C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.94.9.4788
Published
1997-04-29
Pages
4788-93
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC20803
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047343 · United States
NIDDK NIH HHS · DK-02128 · United States
NIDDK NIH HHS · DK-47343 · United States
External Links
PubMed source DOI: 10.1073/pnas.94.9.4788 PMC Full Text View journal details
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