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Suryanarayana Rayapureddi, Jill Norman, Valerie P J Saw, David Abraham, John Kenneth George Dart; The role of IL-13 in the pathogenesis of ocular mucous membrane pemphigoid.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3039.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular mucous membrane pemphigoid (OcMMP), a severe inflammatory autoimmune disease is characterised by conjunctival fibrosis leading to blindness. Current therapies fail to halt the progressive conjunctival scarring and there is a need for novel anti-fibrotic therapies. We previously reported the high expression of Interleukin-13 (IL-13) in OcMMP conjunctiva (Saw et al., Am J Pathol. 2009). We hypothesize that IL-13 plays a role in the pathogenesis of OcMMP, activating human conjunctival fibroblasts (HCF) to promote scarring, and that it may be a new therapeutic target.
HCFs were grown from conjunctival biopsies obtained from OcMMP patients and age-matched controls (5 patients/group). Expression of IL-13 receptors on HCFs was examined by flow cytometry. The effects of IL-13 on HCF function were measured using established fibrogenic assays: cell proliferation (BrdU incorporation), migration (scratch wound assay), collagen gel contraction and myofibroblast differentiation (expression of α-Smooth Muscle Actin by Western blotting and immunofluorescence). Gene expression profiling (Illumina Transcriptome Arrays) was done to identify IL-13 target genes. Cytokine production in response to IL-13 was assessed by Multiplex ELISA of HCF conditioned media.
Both IL-13 receptors (IL-4α/IL-13Rα1; IL13Rα2) are expressed on HCFs with high levels of IL-13Rα1 (both groups) and variable IL13Rα2 expression (control-low; OcMMP-variable). IL-13 dose-dependently (5 - 50ng/ml) inhibits control HCF proliferation (p<0.05 in 4/5) but had no significant effect on OcMMP cells. IL-13 stimulates collagen gel contraction by control HCFs (% change after 7-days; p=0.025) but not by OcMMP cells (p=0.074). IL-13 had no effect on HCF migration or myofibroblast differentiation in either group. Both pro-inflammatory (Interleukin-6, Monocyte Chemoattractant Protein-1) and pro-fibrotic proteins (which regulate collagen biosynthesis and extracellular matrix (ECM) stability) were induced by IL-13 in both groups.
Our current data suggest that, although IL-13 has no direct pro-fibrotic effects on HCFs, IL-13 produced by T-cells may act to promote inflammation and sustain fibrosis through the induction of inflammatory cytokines and proteins involved in ECM synthesis and stability. Taken together, these data suggest that IL-13 inhibition may be an effective topical therapy to limit scarring in OcMMP patients.
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