In Vivo Modulation of Connexins 43 and 26 of Human Epidermis by Topical Retinoic Acid Treatment

Abstract

SUMMARY After 14 weeks of topical application of 0.1% all-trans -retinoic acid to the napes of volunteers, we observed a 2.5-fold increase in the thickness of epidermis, owing to an increase ( p Ͻ 0.001) in the number and size of keratinocytes and the induction of keratin 6. These changes in the differentiation of epidermal keratinocytes were paralleled by an increase in the amount of Cx43, a connexin that is normally expressed in human epidermis, and by the massive induction of Cx26, which is barely detectable in normal interfollicular epidermis, as judged at both the transcript (Northern blotting) and the protein level (immunolabeling). In contrast, retinoic acid treatment did not alter the morphology and connexin pattern of hair follicles or of sebaceous and sweat glands, and did not induce the expression of other connexins (C32, Cx37, Cx40) in either skin adnexae or epidermis. These observations suggest that the expression of two distinct connexins by interfollicular keratinocytes is related to selective changes in the differentiation program of epidermis that are induced by retinoic acid.

Cutting Edge: Lack of Evidence for Connexin-43 Expression in Human Epidermal Langerhans Cells

“…Several explanations could account for this difference, notably the type of skin used, the lot of Ab2 tested, the degree of resolution achievable by immunofluorescence microscopy, and the sensitivity of the detection systems used. Our experiments have confirmed the previous reports of high levels of Cx43 in human keratinocytes (2,3). In this respect, two points are surprising in the putative Cx43 labeling of skin shown in Ref.…”

“…Connexins (Cx) are the structural proteins of GJ (1,2). Cx43 is broadly expressed in tissues and is the most prominent Cx of keratinocytes (2), which intercommunicate through GJ within a normal epidermis (3).…”

“…Connexins (Cx) are the structural proteins of GJ (1,2). Cx43 is broadly expressed in tissues and is the most prominent Cx of keratinocytes (2), which intercommunicate through GJ within a normal epidermis (3). Its presence has also been reported in immune cells, including T and B cells, neutrophils, mast cells, monocytes, and macrophages (4,5).…”

Connexins: a connection with the skin

“…These findings contrast the distinct expression pattern in mouse and rat epidermis, where Cx43 is restricted to basal cells and less differentiated lower spinous cell layers and Cx26 to terminally differentiating spinous and granular cell layers (61,70,80). However, a similar increase and co-expression of Cx26 and Cx43 has been observed when rodent or human epidermis was treated with all-trans retinoic acid or phorbol esters (64,78,81,82). Likewise, analysis of the effect of skin tumor promotors on Cx43, Cx26, and Cx31.1 in Sencar 83 mouse epidermis revealed an induction of Cx26 expression, transiently increased expression of Cx43, and significantly inhibited expression of Cx31.1 (83).…”

“…Cx26 can be detected by immunostaining throughout all layers of the epidermis, where it is localized at the cell membrane of keratinocytes as well as in the cytoplasm, suggesting a disturbance of Cx26 turnover in psoriatic epidermis (73). However, the expression of other Cx, such as Cx37 and Cx31.1, is also induced in psoriasis and EKV (81). Apart from psoriasis, a significant Cx26 expression has been noted in viral warts, and stratified buccal and vaginal epithelia in the basal and suprabasal compartments, where it shows an extensive overlap in distribution with Cx43 (73).…”