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Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury

Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury
Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury
BACKGROUND & AIMS: Interleukin (IL)-12 is believed to modulate local T-cell response in human colitis. A direct functional relationship between IL-12 and tissue injury in human intestine has not been reported. The aim of this study was to examine changes that take place in explant cultures of human fetal gut after stimulation of T cells with anti-CD3 in the presence of exogenous IL-12/IL-18. METHODS: T cells in explants of fetal gut were activated with anti-CD3 antibody and/or IL-12 or IL-18. Mucosal pathology was determined by immunohistochemistry. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to determine cytokine synthesis, and the production of matrix metalloproteinases was analyzed by RT-PCR and Western blotting. RESULTS: Activation of T cells in explants with anti-CD3 antibody elicited very little interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and no tissue injury. Addition of graded doses of IL-12 with anti-CD3 resulted in a significant increase in both IFN-gamma and TNF-alpha. This change was associated with a massive increase in stromelysin-1 expression and severe tissue injury, which was inhibitable by a stromelysin-1 inhibitor. Costimulation of explants with anti-CD3 and IL-18 induced only IFN-gamma and no tissue injury. CONCLUSIONS: IL-12 can convert a physiological T-cell signal into a strong signal with the downstream effect of elevating tissue stromelysin-1 concentration and mucosal degradation.
0016-5085
1069-1077
Monteleone, Giovanni
a289342b-54b5-414a-9e06-aa6b052f91b2
MacDonald, Thomas T.
a6bde8a9-acc4-4128-851f-dd5dbfe28816
Wathen, Neville C.
352e9a51-ce7a-42e4-9a2a-f3ff270f96b8
Pallone, Francesco
32655223-dbe3-4c57-bd7b-149a22bde796
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
Monteleone, Giovanni
a289342b-54b5-414a-9e06-aa6b052f91b2
MacDonald, Thomas T.
a6bde8a9-acc4-4128-851f-dd5dbfe28816
Wathen, Neville C.
352e9a51-ce7a-42e4-9a2a-f3ff270f96b8
Pallone, Francesco
32655223-dbe3-4c57-bd7b-149a22bde796
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242

Monteleone, Giovanni, MacDonald, Thomas T., Wathen, Neville C., Pallone, Francesco and Pender, Sylvia L.F. (1999) Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury. Gastroenterology, 117 (5), 1069-1077. (doi:10.1016/S0016-5085(99)70391-4).

Record type: Article

Abstract

BACKGROUND & AIMS: Interleukin (IL)-12 is believed to modulate local T-cell response in human colitis. A direct functional relationship between IL-12 and tissue injury in human intestine has not been reported. The aim of this study was to examine changes that take place in explant cultures of human fetal gut after stimulation of T cells with anti-CD3 in the presence of exogenous IL-12/IL-18. METHODS: T cells in explants of fetal gut were activated with anti-CD3 antibody and/or IL-12 or IL-18. Mucosal pathology was determined by immunohistochemistry. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to determine cytokine synthesis, and the production of matrix metalloproteinases was analyzed by RT-PCR and Western blotting. RESULTS: Activation of T cells in explants with anti-CD3 antibody elicited very little interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and no tissue injury. Addition of graded doses of IL-12 with anti-CD3 resulted in a significant increase in both IFN-gamma and TNF-alpha. This change was associated with a massive increase in stromelysin-1 expression and severe tissue injury, which was inhibitable by a stromelysin-1 inhibitor. Costimulation of explants with anti-CD3 and IL-18 induced only IFN-gamma and no tissue injury. CONCLUSIONS: IL-12 can convert a physiological T-cell signal into a strong signal with the downstream effect of elevating tissue stromelysin-1 concentration and mucosal degradation.

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Published date: November 1999

Identifiers

Local EPrints ID: 73605
URI: http://eprints.soton.ac.uk/id/eprint/73605
ISSN: 0016-5085
PURE UUID: 8e292008-c1c6-4695-a62d-b36d36527a8b
ORCID for Sylvia L.F. Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 10 Mar 2010
Last modified: 14 Mar 2024 02:45

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Contributors

Author: Giovanni Monteleone
Author: Thomas T. MacDonald
Author: Neville C. Wathen
Author: Francesco Pallone

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