Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling

Seshagiri-Rao Nandula

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Present Address: Diagnostics and Biological Sciences, University of Minnesota, MN, USA.

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Paromita Dey,

Paromita Dey

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

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Kathryn L. Corbin,

Kathryn L. Corbin

Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA

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Craig S. Nunemaker,

Craig S. Nunemaker

Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA

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Harini Bagavant,

Harini Bagavant

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

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Umesh S. Deshmukh,

Umesh S. Deshmukh

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

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Seshagiri-Rao Nandula,

Seshagiri-Rao Nandula

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Present Address: Diagnostics and Biological Sciences, University of Minnesota, MN, USA.

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Paromita Dey,

Paromita Dey

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

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Kathryn L. Corbin,

Kathryn L. Corbin

Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA

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Craig S. Nunemaker,

Craig S. Nunemaker

Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA

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Harini Bagavant,

Harini Bagavant

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

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Umesh S. Deshmukh,

Umesh S. Deshmukh

Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

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First published: 05 June 2012

https://doi.org/10.1111/j.1600-0714.2012.01181.x

Citations: 33

Umesh S. Deshmukh, PhD, Associate Professor of Medicine, University of Virginia, School of Medicine, HSC Box 800746, Charlottesville, VA 22908, USA. Tel: 1 434 924 1130, Fax: 1 434 924 3578, E-mail: [email protected]

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Abstract

Background: Activation of innate immunity through polyinosinic:polycytidylic acid [poly(I:C)] causes acute salivary gland hypofunction. As a major consequence of poly(I:C) treatment is type I interferon (IFN) production, this study was undertaken to investigate their role in salivary gland dysfunction.

Methods: Different strains of mice deficient in either interferon alpha receptor (IFNAR1^−/−) or IL-6^−/−, or IL-10^−/−, or EBI3^−/− were treated with poly(I:C). Salivary gland function was determined by measuring pilocarpine-induced saliva volume. Gene expression levels were measured by real-time PCR. Ca²⁺ mobilization studies were performed using ex-vivo acinar cells.

Results: A single injection of poly(I:C) rapidly induced salivary gland hypofunction in wild-type B6 mice (41% drop in saliva volumes compared to PBS-treated mice). In contrast, the loss of function in poly(I:C)-treated IFNAR^−/− mice was only 9.6%. Gene expression analysis showed reduced levels of Il-6, Il-10, and Il-27 in submandibular glands of poly(I:C)-treated IFNAR^−/− mice. While salivary gland dysfunction in poly(I:C)-treated IL-10^−/− and EBI3^−/− mice was comparable to wild-type mice, the IL-6^−/− mice were more resistant, with only a 21% drop in function. Pilocarpine-induced Ca²⁺ flux was significantly suppressed in acinar cells obtained from poly(I:C)-treated wild-type mice.

Conclusions: Our data demonstrate that a combined action of type I IFNs and IL-6 contributes toward salivary gland hypofunction. This happens through interference with Ca²⁺ mobilization within acinar cells. Thus, in acute viral infections and diseases like Sjögren’s syndrome, elevated levels of type I IFNs and IL-6 can directly affect glandular function.

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Volume42, Issue1

January 2013

Pages 66-72

Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling

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Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling

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