Roles of caspase 1 and extracellular signal-regulated kinase in inflammation-induced inhibition of lacrimal gland protein secretion.
OBJECTIVE
The purpose of the present study was to investigate the roles of caspase 1 and extracellular signal-regulated kinase (ERK) in inflammation-induced inhibition of lacrimal gland secretion.


METHODS
Lacrimal gland inflammation was induced by injection of lipopolysaccharide (LPS; to study the role of caspase 1) or IL-1beta (to study the role of ERK). Lacrimal gland protein secretion was measured using a spectrofluorometric assay. Caspase 1 and ERK activities in the lacrimal gland were measured by immunohistochemistry, Western blotting, or both. Aqueous tear production was measured using phenol red-impregnated cotton threads.


RESULTS
Injection of LPS into the lacrimal gland inhibited neurally and adrenergic agonist-induced protein secretion by 77% and 54%, respectively, and activated caspase 1. The degree of inhibition achieved by LPS was similar to that obtained with injection of IL-1beta. Inhibition of caspase 1 alleviated the inhibitory effect of LPS on lacrimal gland secretion. IL-1beta activated ERK in the lacrimal gland in vitro and in vivo, and this effect was blocked by UO126, an inhibitor of MEK, the ERK-activating enzyme. IL-1beta injection into the lacrimal gland inhibited aqueous tear production by 52% and inhibited neurally and adrenergic agonist-induced protein secretion by 80% and 55%, respectively. UO126 alleviated the inhibitory effect of IL-1beta on aqueous tear production and lacrimal gland protein secretion.


CONCLUSIONS
LPS inhibits lacrimal gland secretion by activating caspase 1, and IL-1beta activates the ERK pathway to inhibit lacrimal gland protein secretion and aqueous tear production.
Department of General Dentistry, Tufts University School of Dental Medicine, Boston, Massachusetts 0211, USA. driss.zoukhri@tufts.edu
Driss
D
Zoukhri
Sunghwan
S
Ko
Paul C
PC
Stark
Claire L
CL
Kublin
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism*; D003607:Dacryocystitis / Q000139:chemically induced / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D053583:Interleukin-1beta / Q000494:pharmacology; D007765:Lacrimal Apparatus / Q000187:drug effects* / Q000201:enzymology; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013666:Tears / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009570:Nitriles; D011994:Recombinant Proteins; C113580:U 0126; C042434:tear proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020170:Caspase 1