Abstract
Keratins form intermediate filaments of the cytoskeleton in keratinocytes and have roles in cell structure, signaling, intracellular transport, and cell death. Oral lichen planus (OLP) is an oral inflammatory disease with derangements in basal keratinocytes and disruption of the basal membrane. Here, we focused on epithelial expression of keratins 8, 18, and 19 because these proteins are known to modulate cell death. Biopsies were taken from buccal oral mucosa of persons with normal oral mucosa (n=10) or atrophic OLP (n=10). Cultured normal oral keratinocytes (n=4) showed expression of mRNA and protein for keratins 8, 18, and 19. Immunohistochemistry showed consistent staining for keratins 8 and 18 in basal keratinocytes of normal oral mucosa. In OLP, staining for keratin (K)8 was mostly negative and staining for K18 was weak. Keratin 19 was expressed irregularly in most biopsies of normal oral mucosa and not at all in OLP. Several mononuclear leukocytes in the cellular infiltrate showed membrane staining for K8 and K18. Positive staining for K16 confirmed partial collapse of the basal cell layer in OLP. The basal cell niche in OLP therefore appeared to be partly populated with keratinocytes demonstrating a higher degree of differentiation (K8- K18- K19- K16+ ); consequently, such areas may be more susceptible to the action of cell death factors released from the cell infiltrate as a result of lacking the protective, normal keratin present in the basal epithelial cell layer of normal oral mucosa.
Highlights
Previous investigations have shown that epithelial expression of keratins is altered in Oral lichen planus (OLP) compared with normal oral mucosa and this can affect the functions mentioned above: keratin 1 (K1)/keratin 10 (K10) [17,18,19], keratin 14 (K14) [19, 20], keratin 6 (K6)/keratin 16 (K16), and keratin 19 (K19) [19] are reported to be upregulated in OLP, whereas keratin 4 (K4) [21], K4/keratin 13 (K13) [18, 19], keratin 5 (K5)/keratin 15 (K15) [19], and K19 [22, 23] are reported to be downregulated
The keratin 8 (K8)/keratin 18 (K18) and K8/K19 protein complexes are foremost expressed in single-layer epithelia, such as in the intestine, but they can be expressed in more complex epithelia [4]
The latter was found to be the case for oral buccal mucosa as we detected K8, K18, and K19 protein in cells from primary oral keratinocyte cultures, from normal oral mucosa, by western blotting and immunocytofluorescence, and KRT8, KRT18, and KRT19 mRNAs by RT-qPCR
Summary
Deficiencies in expression of K8, K18, and K19 have been found to alter intracellular cell-death signaling, and defective variants of these keratins are associated with diseases in which abnormal cell death is seen (e.g., in the liver, where hepatocellular ballooning and Mallory–Denk body formation can be found) [10] Such cell-death regulation can take place at different levels, for example, by caspase binding and activation of the death effector domain containing DNA binding domain (DEDD), ensuring degradation of substrates in an ordered manner [11]; sequestration of intracellular scaffolding proteins that participate in death receptor signaling [12, 13]; modulation of TNF-induced nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-jB) activation [8]; targeting of Fas receptors to the cell surface [13]; and protection of mitochondrial function [14]. As cytokines can regulate expression of several keratins [26], we tested the hypotheses that inflammatory cytokines from OLP can be modulators for K8, K18, and K19 expression
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