Stimulatory effects of dibutyryl cyclic adenosine monophosphate on cytokine production by keratinocytes and fibroblasts

Abstract

Background Clinical studies have shown that ointment containing dibutyryl cyclic adenosine monophosphate (DBcAMP) promotes wound healing.Objectives We aimed to elucidate the mechanisms of the beneficial effect of DBcAMP in wound healing. Methods An investigation was made of the effects of DBcAMP on in vitro cytokine release from cultured keratinocytes and fibroblasts derived from normal human skin. Results DBcAMP stimulated keratinocyte proliferation through increased interleukin (IL)-6 production by fibroblasts, and transiently enhanced production of transforming growth factor (TGF)-b1 by fibroblasts at an early stage of incubation. DBcAMP also stimulated fibroblast proliferation, resulting in further increases in IL-6 and TGF-b1. Conclusions We conclude that this series of stimulative actions on cytokine secretion, together with the facilitation of cell proliferation, contribute to the effects of DBcAMP on the healing of skin ulcers.

Effect of parathyroid hormone‐related protein on fibroblast proliferation and collagen metabolism in human skin

“…Our result is in conflict with a recent study of Zhou et al. who reported that dbcAMP significantly enhances fibroblast proliferation (10).…”

“…Because in the study of Zhou et al. dbcAMP was shown to stimulate the production of TGF‐β by fibroblast (10), it cannot be excluded that the proliferative effect of dbcAMP they observed could be mediated by an autocrine effect of TGF‐β on fibroblasts themselves. If this should be the case, TGF‐β production could not be occurred in our cultures, where fibroblasts were grown in serum‐free medium 24 h before and during the treatment with PTHrp.…”

“…Some experimental evidences suggest that PTHrp could be involved in the regulation of both processes, acting on both cell types. With regard to cell proliferation, it has been shown that incubation of fibroblasts with dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP, results in an increased release of IL‐6 and TGF‐β1, which stimulate and inhibit keratinocytes proliferation, respectively (10). Because PTHrp is known to act on fibroblasts via cAMP (9,11), the described effect of dbcAMP could be interpreted as a mimic effect of PTHrp in vivo .…”

“…Moreover, TGF‐β1 (an important modulator of cellular growth and differentiation) not only regulates keratinocytes activity, but also acts on fibroblasts promoting proliferation and collagen synthesis (10).…”

Influence of various treatments including povidone‐iodine and healing stimulatory reagents in a rabbit ear wound model

“…PGE1 ointment was effective in treating patients with incurable peripheral ischaemic ulcers (34) and burn patients presenting rapid epithelialisation (11). DBcAMP stimulated the growth of keratinocytes and fibroblasts by inducing secretion of several cytokines (35,36), and its topical application resulted in significant acceleration of wound healing in an animal model (12). Clinical study of this ointment has also shown its benefits in the treatment of pressure ulcers (37).…”