Gastroenterology

Gastroenterology

Volume 115, Issue 4, October 1998, Pages 856-865
Gastroenterology

Alimentary Tract
Subtherapeutic corticosteroids potentiate the ability of interleukin 10 to prevent chronic inflammation in rats,☆☆,

https://doi.org/10.1016/S0016-5085(98)70257-4Get rights and content

Abstract

Background & Aims: Interleukin (IL)-10, which inhibits macrophages and T-helper lymphocyte type 1 (TH1) lymphocytes, attenuates chronic granulomatous inflammation induced by bacterial cell wall polymers. This study determines whether corticosteroids enhance the protective effects of IL-10 in cultured peripheral blood mononuclear cells (PBMNCs) and in vivo when started before or after the onset of experimental chronic granulomatous inflammation. Methods: Intestines of Lewis rats were injected intramurally with streptococcal peptidoglycan-polysaccharide (PG-APS) polymers. Daily murine recombinant IL-10 and/or dexamethasone (DEX) therapy was started 12 hours before or at several intervals after PG-APS injection. Results: IL-10 plus corticosteroids additively inhibited IL-1β secretion in human PBMNCs but preserved the beneficial IL-1RA/IL-1β ratio induced by IL-10. IL-10 started before PG-APS injection significantly attenuated intestinal and extraintestinal inflammation, with even more pronounced effects in combination with subtherapeutic doses of DEX. The combination of DEX decreased the effective dose of IL-10 by at least one half. After onset of systemic inflammation using doses effective for prevention, IL-10 monotherapy had nearly no benefit and DEX plus IL-10 was similar to the mild therapeutic effect of DEX alone. Conclusions: The combination of IL-10 and corticosteroids allows lower doses of both agents in preventing chronic intestinal and systemic inflammation. However, timing of IL-10 administration is a critical variable in regulating inflammation.

GASTROENTEROLOGY 1998;115:856-865

Section snippets

Animals and reagents

Female, inbred, specific pathogen–free Lewis rats (145-155 g) were obtained from Charles River Laboratories (Raleigh, NC). Rats were fed Agway Prolab rat chow (Agway Inc., Syracuse, NY) ad libitum and were weighed daily. All rat experiments were conducted in accord with the highest standards of humane animal care as outlined in the National Institutes of Health's “Guide for the Care and Use of Laboratory Animals” and were approved by the University of North Carolina Institutional Animal Care

The effects of IL-10 and DEX on IL-1 and IL-1RA in vitro

To investigate whether the combination of IL-10 and DEX would exceed the anti-inflammatory potential of either agent alone, we first determined the effects of these drugs on the IL-1RA/IL-1β ratio in supernatants of LPS-stimulated human PBMNCs (Figure 1).

. Effect of graded doses of IL-10 and DEX alone or in combination on spontaneous and LPS-stimulated IL-1β and IL-1RA secretion by human PBMNCs. Cells were cultured for 24 hours either in the absence (unstimulated) or presence (stimulated) of 1

Discussion

We show in this study that IL-10 and DEX have additive anti-inflammatory effects in vivo and in vitro. In agreement with our recently published results,17 pretreatment with high doses of IL-10 alone completely prevented arthritis and significantly attenuated intestinal granulomatous inflammation. The combination of IL-10 and DEX is clinically relevant, because corticosteroids are an important mainstay of IBD therapy18 and intravenous IL-10 was effective in a small trial of patients with

Acknowledgements

The authors thank Roger Brown for preparation of PG-APS, Julie Vorobiov and Lisa Holt for technical support, and Susie May and Beverly Vought for secretarial assistance.

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    Address requests for reprints to: R. Balfour Sartor, M.D., Division of Digestive Diseases & Nutrition, UNC School of Medicine, Room 030 Glaxo Building, CB 7080, Chapel Hill, North Carolina 27599-7080. e-mail: [email protected]; fax: (919) 966-7468.

    ☆☆

    Supported by grants He 2379/1-1 and Bo1340/1-1 from the Deutsche Forschungsgemeinschaft, the National Institutes of Health grants DK 40249 and DK 34987, and Schering-Plough Research Institute.

    Dr. Herfarth's current address is: Klinik and Poliklinik für Innere Medizin I, Universität Regensburg, Germany.

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