Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling.
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. Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.
Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Seshagiri-Rao
SR
Nandula
Paromita
P
Dey
Kathryn L
KL
Corbin
Craig S
CS
Nunemaker
Harini
H
Bagavant
Umesh S
US
Deshmukh
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D005260:Female; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007370:Interferon Type I / Q000096:biosynthesis / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000276:immunology; D012463:Saliva / Q000378:metabolism; D013363:Submandibular Gland / Q000187:drug effects* / Q000378:metabolism; D014987:Xerostomia / Q000139:chemically induced / Q000276:immunology*
C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D020381:Interleukin-17; D015850:Interleukin-6; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D011070:Poly I-C