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. 1998 Mar;82(3):318-22.
doi: 10.1136/bjo.82.3.318.

Orbital fibroblast chemokine modulation: effects of dexamethasone and cyclosporin A

M A Burnstine  1 , S G Elner, V M Elner
Affiliations

Orbital fibroblast chemokine modulation: effects of dexamethasone and cyclosporin A

M A Burnstine et al. Br J Ophthalmol. 1998 Mar.

Abstract

Aim: Orbital inflammation is common, but the mechanisms underlying leucocytic infiltration of orbital tissue are poorly understood. Human orbital fibroblasts (OF) express chemokines, interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1), when exposed to proinflammatory cytokines. The effect of dexamethasone (DEX) and cyclosporin A (CSA) on OF IL-8 and MCP-1 were examined.

Methods: Cultured human OF were incubated with recombinant interleukin 1 beta (rIL-1 beta; 0.2, 2.0, 20 ng/ml) alone or incubated with rIL-1 beta and DEX (10(-8), 10(-7), 10(-6) M) or CSA (3, 30, 300 ng/ml) for 24 hours. ELISA and northern blot analyses were performed to determine OF IL-8 and MCP-1 protein secretion and mRNA expression, respectively.

Results: OF lacked constitutive IL-8 or MCP-1 expression, but secreted significant amounts of these chemokines and expressed substantial steady state mRNA for both chemokines upon rIL-1 beta stimulation. DEX caused dose dependent inhibition of IL-1 induced IL-8 (p < 0.001) and MCP-1 (p < 0.05) secretion and mRNA expression at all concentrations of rIL-1 beta. CSA enhanced IL-1 induced OF IL-8 (p < 0.001) and suppressed rIL-1 beta induced OF MCP-1 (p < 0.05) secretion when lower doses of rIL-1 beta were used. These effects on secreted chemokines at different concentrations of rIL-1 beta and immunomodulating agents were corroborated by steady state OF IL-8 and MCP-1 mRNA expression.

Conclusions: DEX is a potent inhibitor of OF IL-8 and MCP-1. In contrast, CSA enhances IL-1 induced OF IL-8 and suppresses OF MCP-1. These observations may explain the relative lack of CSA effectiveness in human orbital diseases that respond to corticosteroids.

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Figures

Figure 1
Figure 1
Dose dependent effects of dexamethasone and cyclosporin A on rIL-1β induced IL-8 secretion by orbital fibroblasts detected by ELISA. *Denotes p<0.001 compared with rIL-1β stimulated control.
Figure 2
Figure 2
Dose dependent effects of dexamethasone and cyclosporin A on rIL-1β induced MCP-1 secretion by orbital fibroblasts detected by ELISA. *Denotes p<0.05 compared with rIL-1β stimulated control.
Figure 3
Figure 3
Representative northern blots revealing the effects of dexamethasone (DEX) and cyclosporin A (CSA) on rIL-1β induced (20 ng/ml) IL-8 and MCP-1 mRNA expression in human orbital fibroblasts at 24 hours. Equivalent total cellular RNA loading per lane is demonstrated by the electrophoretic profile (below) of 18s and 28s rRNA in all lanes, except the high dose CSA lane in which cell death occurred from cyclosporin toxicity.
Figure 4
Figure 4
Representative blots revealing the effects of dexamethasone (DEX) and cyclosporin A (CSA) on OF IL-8 and MCP-1 mRNA expression in human orbital fibroblasts at 24 hours in response to rIL-1β OF stimulation (2.0 ng/ml). Equivalent total cellular RNA loading per lane is demonstrated by the electrophoretic profile (below) of 18s and 28s rRNA in all lanes. Similar results were found with rIL-1β (0.2 ng/ml) stimulation (data not shown).
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