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D Byon, CL Kublin, D Zoukhri; Mechanisms of Proinflammatory Cytokines-Induced Inhibition of Lacrimal Gland Secretion . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3144.
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Purpose: To investigate the role of the stress-activated protein kinase Jun NH2-terminal kinase (JNK1/2), the mitogen-activated protein kinase (MAPK also known as p42/44 ERK) and the constitutive and inducible nitric oxide synthases (cNOS and iNOS) in proinflammatory-induced inhibition of lacrimal gland secretion. Method: Recombinant human (rh) IL-1α, rhIL-1ß (1 µg each), lipopolysaccharide (LPS, 25 µg) or saline (vehicle) were injected (2 µl) into the lacrimal glands of anesthetized female BALB/c mice. Twenty-four hours later, lacrimal glands were removed and lobules were prepared. Lobules from the same animal were divided in half and used to measure peroxidase secretion or homogenized for western blotting analyses. For peroxidase secretion, lobules were stimulated for 20 min with high KCl (75 mM, to stimulate lacrimal gland nerve endings). For western blotting, the membranes were blotted either with antibodies against phosphorylated (activated) or total JNK1/2 and p42/44 ERK (to normalize for equal loading of the gels) and with antibodies against cNOS and iNOS. Results: KCl-induced peroxidase secretion was inhibited 65%, 64%, and 78% by rhIL-1α, rhIL-1ß and LPS, respectively.Compared to saline injected animals, cytokines or LPS treatment resulted in a 2- to 4-fold increase in JNK and ERK activity. Furthermore, whereas iNOS protein was not detected in saline-injected animals, this protein was induced after cytokine and LPS injection. In contrast, the amount of cNOS was not affected by either cytokine or LPS treatment. Conclusion: Our results show that, concomitant with cytokine or LPS-induced inhibition of neurally stimulated lacrimal gland secretion, there is increased expression of iNOS, probably through activation of JNK and/or ERK. These results suggest that inflammation-induced expression of iNOS and production of nitric oxide might be responsible for the impaired secretory function of the lacrimal gland associated with autoimmune xerophthalmia.
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