Topical retinoic acid alters the expression of cellular retinoic acid‐binding protein‐I and cellular retinoic acid‐binding protein‐II in non‐lesional but not lesional psoriatic skin

Abstract

Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.

Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt

“…CRABPI is expressed in basal and suprabasal keratinocytes (Karlsson et al, 2002) and regulates retinoic acid degradation (Dong et al, 1999). CRABPII is expressed in suprabasal keratinocytes (Karlsson et al, 2002) and regulates retinoic acid signalling (Dong et al, 1999). CRABPII is reported to sensitise epithelial cells to retinoic acid-induced growth arrest (Budhu and Noy, 2002) and its upregulation during keratinocyte differentiation (ChatellardGruaz et al, 1998) may thus contribute to withdrawal of keratinocytes from the cell cycle.…”

“…CRABPI and II are retinoic acid binding proteins that are known to have important functions within the skin (Elder et al, 1993). CRABPI is expressed in basal and suprabasal keratinocytes (Karlsson et al, 2002) and regulates retinoic acid degradation (Dong et al, 1999). CRABPII is expressed in suprabasal keratinocytes (Karlsson et al, 2002) and regulates retinoic acid signalling (Dong et al, 1999).…”

Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways

“…Although the authors did not explore the mechanism of inhibition, their results are very similar to ours. Furthermore, in a recent study we reported failure of exogenous RA to induce CRABPII in psoriatic skin lesions [25], where IFNγ is markedly increased due to the inflammatory process [35].…”

“…Human foreskin epidermal keratinocytes were obtained from Cascade Biologics, used in combination with PMA or IFNγ for 16 h. Nuclear cell extracts were prepared as previously described and the protein concentration was determined [25]. Total cell protein extracts were prepared by adding RIPA buffer containing protease inhibitors to cell cultures, transferring the lysates to microcentrifuge tubes and keeping them on ice (+4 0 C) for 30 min.…”

“…Third, squamous cell carcinomas frequently display reduced RARγ expression [21,22], and the RAR and RXR levels are progressively suppressed during malignant transformation of human epidermis [10]. Fourth, studies of psoriatic epidermis, characterized by abnormal differentiation and hyperproliferation, have disclosed reduced mRNA expression of RARα and RXRα [23] and increased expression of CRABPII [24,25] that fails to respond to RA treatment [25]. Nonetheless, RArelated drugs (i.e.…”