Transforming growth factor-β/Smad - signalling pathway and conjunctival remodelling in vernal keratoconjunctivitis (original) (raw)

2010, Clinical & Experimental Allergy

Background Vernal keratoconjunctivitis (VKC) is a chronic ocular allergic inflammation characterized by corneal complications and the formation of giant papillae. Sma-and Madrelated proteins (Smad) modulate extracellular matrix gene expression during wound healing, inflammation and tissue remodelling. Objective To investigate the relationship between allergic inflammation and TGF-b/Smad signalling pathway, expression in VKC patients and in primary cultured conjunctival fibroblasts exposed to mediators found previously over-expressed in VKC. Methods Smad-2,-3,-7, phospho-(p)Smads, TGF-b1 and-b2 were evaluated in the conjunctiva of normal subjects (CT) and VKC patients by immunohistochemistry. The expression of Smads, pro-collagen I (PIP), TGF-b1,-b2, mitogen-activated protein kinase (p38/MAPK), c-Jun Nterminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) were also determined in conjunctival fibroblast cultures exposed to histamine, IL-4,-13, TGF-b1, IFN-g and TNF-a using immunostaining or RT-PCR. Results Immunostaining for Smad-2,-3, pSmad-2,-3, TGF-b1,-b2 and PIP was significantly increased in VKC stroma compared with CT. In conjunctival fibroblast cultures, Smad-3 and PIP were stimulated by histamine, IL-4,-13 and TGF-b1 exposure, while PIP was reduced by IFN-g, and TNF-a mRNA expression of Smad-3 was increased by histamine, while Smad-7 was reduced by IL-4. In addition, histamine, IL-4 and TNF-a increased JNK and ERK1/2 expression. Conclusion and Clinical Relevance The TGF-b/Smad signalling pathway is over-expressed in VKC tissues and modulated in conjunctival fibroblasts by histamine, IL-4, TGF-b1 and TNF-a. These mechanisms may be involved in fibrillar collagen production, giant papillae formation and tissue remodelling typical of VKC and might provide new therapeutic targets for its treatment.