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L. Motterle, P. Brun, B. Zavan, A. Di Stefano, F. Piliego, I. Fregona, A. Leonardi; TGF-β/SMAD Signaling Pathway as a Tissue Remodeling Mechanism in Vernal Keratoconjunctivitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6318.
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Tissue remodeling is a consequence of chronic allergic inflammation. We previously found that the Smad signaling pathway is over-expressed in tissues of vernal keratoconjunctivitis (VKC). Here we further investigated the presence of phosphorylated (p)Smad and TGF-β in VKC tissues. In addition, mRNA expression of TGF-β/Smad and mitogen-activated protein kinase was evaluated in fibroblast cultures exposed to histamine, Th1- and Th2-type cytokines.
pSmad-2, -3, -7, TGF-β1 and TGF-β2 were evaluated in conjunctiva from 6 normal subjects (CT) and 9 VKC patients by immunohistochemistry. The mRNA expression of Smads, TGF-β1, TGF-β2, mitogen-activated protein kinase (p38/MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) were also determined in conjunctival fibroblast cultures exposed to histamine, IL-4, IL-13, IFN-γ and TNF-.
Immunostaining for pSmad-2, -3, TGF-β1 and -β2 was significantly increased in VKC tissues compared to CT, while the inhibitory pSmad-7 was unchanged. In conjunctival fibroblast cultures, histamine, IL-4 and TNF- increased the expression of Smad-3 and -7 by 2 and 3 fold, respectively. IL-4 increased TGF-β1 expression, histamine increased TGF-β2 and TNF- increased both TGF-β1 and TGF-β2. In contrast, IFN-γ reduced the expression of Smad-3 and TGF-β1. In addition, histamine, IL-4 and TNF- increased JNK and ERK1/2 expression by 3 fold.
The TGF-β/Smad signaling pathway is over-expressed in VKC tissues and stimulated in conjunctival fibroblasts by histamine, IL-4 and TNF-. These mechanisms may be involved in the tissue remodeling typical of this disease.
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