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PMID: 9746596 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Intestinal secretory factor released by macrophages stimulated with Clostridium difficile toxin A: role of interleukin 1beta.

Infection and immunity ·Vol. 66 ·No. 10 ·1998-10-00 ·Pages 4910-6

Rocha MF, Soares AM, Flores CA, Steiner TS, Lyerly DM, Guerrant RL, Ribeiro RA, Lima AA

Abstract

Clostridium difficile toxin A is associated with enterocolitis in animals and humans. However, the mechanisms of its secretory and damaging effects are not totally understood. In this work, we examined the intestinal secretion of electrolytes and water caused by supernatants from macrophages stimulated with toxin A in rabbit ileal mucosa mounted in Ussing chambers. We also investigated the mechanism by which the intestinal secretory factor (ISF) is released from stimulated macrophages. Supernatants from macrophages stimulated with toxin A caused potent intestinal secretion (change in short-circuit current [DeltaIsc], 76 microA x cm-2; P < 0.01). The release of the ISF was pertussis toxin sensitive (reduction, 61%; P < 0.01) and was also reduced (P < 0.05) by a protein synthesis inhibitor (67%), protease inhibitors (57%), a phospholipase A2 inhibitor (54%), a cyclo-oxygenase inhibitor (62%), a dual cyclo- and lipoxygenase inhibitor (48%), a platelet-activating factor (PAF) receptor antagonist (55%), and tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors (48%). However, this release was not inhibited by a lipo-oxygenase inhibitor. Monoclonal anti-interleukin 1beta (IL-1beta) but not anti-IL-1alpha antibody blocked (72%; P < 0.01) the secretory action of the ISF, as did recombinant human IL-1 receptor antagonist (80%; P < 0.01). High levels of IL-1beta (3,476 pg/ml) were detected by an enzyme-linked immunosorbent assay in the above supernatants. Furthermore, the addition of IL-1beta to the serosal side caused a potent secretory effect (DeltaIsc, 80 microA x cm-2; P < 0.01). These results show that macrophages stimulated with toxin A release an ISF capable of provoking intestinal secretion. The regulation of this factor is dependent upon the activation of the G protein. In addition, prostaglandins, PAF, and TNF-alpha are involved in the release of the ISF. We conclude that IL-1beta is probably the ISF released by macrophages in response to toxin A.

MeSH Terms
Animals Bacterial Toxins Enterotoxins/pharmacology Female GTP-Binding Proteins/metabolism Ileum/immunology Immunologic Factors/metabolism Interleukin-1/metabolism Macrophages/immunology Male Models, Immunological Platelet Activating Factor/immunology Rabbits Rats Signal Transduction Tumor Necrosis Factor-alpha/metabolism Water-Electrolyte Balance/drug effects
Chemicals
Bacterial Toxins Enterotoxins Immunologic Factors Interleukin-1 Platelet Activating Factor Tumor Necrosis Factor-alpha tcdA protein, Clostridium difficile GTP-Binding Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Rocha M F
Department of Physiology and Pharmacology, Clinical Research Unit-HUWC, Health Sciences Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
Soares A M
Flores C A
Steiner T S
Lyerly D M
Guerrant R L
Ribeiro R A
Lima A A
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Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.66.10.4910-4916.1998
Published
1998-10-00
Pages
4910-6
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC108607
Subset
IM
Grants
NIAID NIH HHS · P50 AI030639 · United States
NIAID NIH HHS · U01 AI026512 · United States
NIAID NIH HHS · P01-AI-26512 · United States
External Links
PubMed source DOI: 10.1128/IAI.66.10.4910-4916.1998 PMC Full Text View journal details
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