TCTP is a highly conserved, ubiquitously expressed protein involved in multiple biological activities, including apoptosis . An extensive review of the literature showed that previous studies on TCTP in the cornea used proteomics techniques were limited to cultured keratocytes . In the present study we demonstrated the presence of TCTP in human corneal tissue by RT-PCR and immunoblotting, and confirmed these findings by immunohistochemistry using an antibody against TCTP. Since apoptosis plays a key role in HSK and is controlled by TCTP, we also attempted to find a pathogenic correlation between TCTP and HSK, evaluating TCTP expression in corneal samples with HSK. TCTP inhibited the proapoptotic proteins Bax and BCLxL, promoters of membrane attack complex (MAC) pore formation via dimerization of the mitochondrial membrane. TCTP inserts itself in the mitochondrial membrane, preventing Bax from dimerizing. This inhibits MAC pore formation and prevents any flux of apoptosis promoting factors into the cell. TCTP also binds to Mcl-1, stabilizing it and enhancing its anti-apoptotic activity. In addition, TCTP was shown to bind p53 and prevent apoptosis by destabilizing the protein and repressing transcription of p53 . A correlation was found between the degree of inflammation and expression of TCTP in corneal epithelium, as well as in inflammatory infiltrate in HSK patients with active disease . In the case of mild inflammation, we found low expression of TCTP, limited to neovessels and keratinocytes. These results suggest a double role of TCTP in herpes keratitis: as an antiapoptotic protein in corneal cells and as a cytokine-like protein in the stroma, where TCTP may be secreted by inflammatory cells, probably monocytes, in the extracellular milieu. Apoptosis has been shown to limit viral invasion: corneal infection with wild-type virus results in apoptosis of a number of infected epithelial cells . Primary herpes simplex virus-1 (HSV-1) corneal infection stimulates apoptosis of anterior keratocytes in the stroma underlying the site of epithelial injury. TCTP may modulate the keratocyte apoptotic response, limiting stromal damage as well as triggering the keratocyte apoptotic response via soluble mediators released by epithelial injury secondary to corneal HSV-1 infection. Considering the importance of apoptosis as a general mechanism for eliminating normal and pathologically altered cells, manipulation of apoptosis may offer new possibilities for treating HSK.
We also found a huge amount of TCTP in the extracellular stroma of actively inflamed HSK, which is in line with previous studies on broncho-alveolar lavage fluids of patients with eosinophilic pneumonia and asthma [27, 28]. A mechanism by which extracellular TCTP might intervene through cytokine-like activity in the complex pathogenesis of HSK is by regulating the immune-mediated response to herpes simplex virus. In fact, HSK is currently thought to be an immune-mediated disease. CD4 positive Th1 cells are involved in the development of inflammatory HSK corneal lesions: infiltration of CD4 positive Th1 cells into the cornea causes release of cytokines, mainly interleukin (IL)-2 and interferon (IFN)-γ, which elicit an inflammatory response and recruit neutrophils and macrophages. TCTP is known to inhibit the release of IL-2 in human peripheral blood T cells and Jurkat T cells  and a role of TCTP in the modulation of T regs apoptosis/survival was recently demonstrated .
Repair of damage after each infection progressively impairs the biomechanical properties of the cornea. The repair process or wound healing of corneal epithelium is complex, including cell migration, proliferation and differentiation, all of which depend on calcium-mediated signals . Calcium concentrations vary during wound healing, thus inducing variations in cell motility, morphology and adhesion that are all essential to the process . Calcium levels are regulated by TCTP .