Cytokeratin 5 and its partner cytokeratin 14 form dimers that help give tissue its integrity. Without the presence of these Cabozantinib ic50 cytokeratins, tissue becomes fragile and small injuries can cause tissue to fall apart and blisters to form. These cytokeratins have also been shown to be enhanced in hyperproliferative situations such

as wound healing [33, 39]. These data suggest that ZDV treatment impairs the ability of oral tissue to heal itself. In this study, ZDV treatment induced the expression of cytokeratin 10, particularly at the 6-, 12- and 24-h time-points (Figs 5 and 8). Increased levels of cytokeratin 10 in drug-treated gingival epithelium may be an attempt by the tissue to protect itself against damage caused by ZDV [31, 40, 41]. Additionally, it has been shown that cytokeratin 10 is more strongly expressed in both oral lesions and hyperproliferative epidermis compared

with ordinary epidermis [42]. Thus, the elevated levels of cytokeratin 10 may be linked to the proliferative effect of ZDV on treated rafts. Additionally, the normal balance of cytokeratin proliferation and differentiation may be disrupted upon injury and under pathological conditions [43-45]. Involucrin expression is induced by the same pathway as cytokeratin 5. In addition to a change in cytokeratin expression, envelope formation is a hallmark of terminal differentiation. In order for the envelope to be formed correctly, the envelope precursors and transglutaminase, the enzyme responsible for the assembly of the envelope, must be expressed HIF inhibitor not at the correct time and level during the differentiation process [37]. Involucrin is a component of the cornified envelope. Involucrin is specifically expressed in the suprabasal layers of the epidermis [37], while in the spinous and granular layer, involucrin accumulates as a non-cross-linked precursor. During the final stages of keratinocyte differentiation, involucrin becomes cross-linked to other proteins to form the cornified envelope [37]. Involucrin expression, like that of cytokeratin 5, is regulated by the specificity protein (Sp1) [37], and in our study the expression

of involucrin, like that of cytokeratin 5, was decreased in response to ZDV treatment. A lack of involucrin available for cross-linking may explain the lack of a vaculated, cornified layer seen in ZDV-treated tissues and may account for the fragility of oral tissues in patients on HAART. Induction of cytokeratin 6 expression in protease inhibitor-treated rafts [26, 27], as well as a slight increase in cytokeratin 10 expression in ZDV-treated tissues, suggested the possibility that HAART drugs, including ZDV, were causing damage to the gingival epithelium. To examine this possibility, we looked at the expression patterns of cytokeratin 6, a wound-healing keratin which is activated in response to injury in the suprabasal layer of stratified epithelium.