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Inflammation induced changes in adenosine 3′,5′-cyclic monophosphate production by ciliary epithelial cell bilayers

Authors
Journal
Experimental Eye Research
0014-4835
Publisher
Elsevier
Publication Date
Volume
60
Issue
2
Identifiers
DOI: 10.1016/s0014-4835(95)80007-7
Keywords
  • Adenosine 3′
  • 5′-Cyclic Monophosphate
  • Interleukin-1
  • Tumor Necrosis Factor
  • Anterior Uvea
  • Ciliary Epithelium
  • Endotoxin
  • Uveitis
Disciplines
  • Biology

Abstract

Despite extensive evidence implicating the cytokines interleukin-1 (IL-1) and tumor necrosis factor- α (TNF α) in the intraocular inflammatory response, little is known about their effects on signal transduction in anterior uveal tissue. Since these cytokines have been shown to alter the adenylyl cyclase system in nonocular tissues, we tested the hypothesis that IL-1 β and TNF α affect the anterior uvea by altering production of the intracellular second messenger adenosine 3′,5′-cyclic monophosphate (cAMP) in ciliary epithelial bilayers. This was accomplished by measuring the levels of cAMP in bilayers ex vivo, following intraocular inflammation induced by intravitreal injection of IL-1 β, TNF α or bacterial endotoxin, and in vitro, following exposure to IL-1 β, TNF α or bacterial endotoxin. Although cAMP production was enhanced in bilayers from IL-1 β-, TNF α- or endotoxin-inflamed eyes, ex vivo, exposure of normal bilayers to IL-1 β (15 U ml −1), TNF α (20 U ml −1), or a low concentration of endotoxin (0·01 μg ml −1) for 4 hr, in vitro, had no effect on cAMP production. The inability of IL-1 β, TNF α, or the low concentration of endotoxin to increase cAMP production by bilayers, in vitro, suggests that the enhanced cAMP production observed with inflamed bilayers, ex vivo, was not due to a direct action of these inflammatory agonists on the ciliary epithelial bilayer. Although direct exposure to cytokines or endotoxin did not change cAMP production, treatment with IL-1 β, TNF α, or a higher concentration of endotoxin (1 μg ml −1) did affect signal transduction mechanisms. For example, exposure to IL-1 β, TNF α, or a higher concentration of endotoxin rendered normal bilayers unresponsive to isoproterenol. A similar absence of response to isoproterenol was also seen with bilayers from TNF α-inflamed eyes. This insensitivity to β-receptor stimulation is apparently a consequence of receptor downregulation or functional uncoupling of the receptor from the transducing G protein, since in each case of isoproterenol insensitivity, bilayers exhibited forskolin responses indistinguishable from the appropriate control tissues. Since cAMP production by the epithelial cell bilayer was increased in three different models of intraocular inflammation, augmented production of this second messenger is likely to occur during uveitis of diverse etiology. Enhanced cAMP production by inflamed epithelial bilayers may contribute to some general aspect of the uveitic response such as altered intraocular pressure or possibly serve to enhance efflux of fluid from swollen anterior uveal tissue.

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