c-Jun NH2-terminal kinase mediates interleukin-1beta-induced inhibition of lacrimal gland secretion.
Sjögren's syndrome, an inflammatory disease affecting the lacrimal and salivary glands, is the leading cause of aqueous tear-deficient type of dry eye. We previously showed that interleukin-1beta (IL-1beta) protein is up regulated in the lacrimal gland of a murine model of Sjögren's syndrome and that exogenous addition of this cytokine inhibits neurotransmitter release and lacrimal gland protein secretion. In the present study we investigated the role of c-Jun NH2-terminal kinase (JNK) in IL-1beta-mediated inhibition of lacrimal gland secretion and tear production. In vitro, IL-1beta induced a time-dependent activation of JNK with a maximum 7.5-fold at 30 min. SP600125, a JNK inhibitor, inhibited, in a concentration-dependent manner, IL-1beta-induced activation of JNK with a maximum of 87% at 10(-4) m. In vivo, IL-1beta stimulated JNK and the expression of the inducible isoform of nitric oxide synthase (iNOS). IL-1beta inhibited high KCl and adrenergic agonist induced protein secretion by 85% and 66%, respectively. SP600125 alleviated the inhibitory effect of IL-1beta on KCl- and agonist-induced protein secretion by 79% and 47%, respectively, and completely blocked the expression of iNOS. Treatment for 7 days with SP600125 increased tear production in a murine model of Sjögren's syndrome dry eye. We conclude that JNK plays a pivotal role in IL-1beta-mediated inhibition of lacrimal gland secretion and subsequent dry eye.
Zoukhri
Driss
D
Department of General Dentistry, Tufts University School of Dental Medicine and Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
Macari
Elizabeth
E
Choi
Sun H
SH
Kublin
Claire L
CL
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D003864:Depression, Chemical; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D007700:Kinetics; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000378:metabolism; D013666:Tears / Q000378:metabolism
D000873:Anthracenes; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; C432165:pyrazolanthrone; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases