Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Abstract

Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A 2B receptors, human epidermal keratinocytes also express A 2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A 2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A 2A receptors by CGS-21680 induces keratinocyte proliferation via p38emitogen-activated protein kinase activation. Adenosine and selective A 2A and A 2B agonists presented anti-inflammatory profiles independent of adenosine receptors but mediated by membrane phosphatase activation. Finally, keratinocyte exposure to diverse inflammatory cytokines altered adenosine receptor expression by reducing A 2B and increasing A 2A , a pattern also observed in psoriatic epidermis. Because increased epidermal turnover and inflammatory response are characteristics of psoriatic disease, further studies are needed to assess the role and consequences of the altered adenosine receptor expression in lesional and nonlesional psoriatic keratinocytes.

Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways

“…At least under normal conditions [77] the main adenosine receptor in keratinocytes is A 2B [21,22], the activation of which inhibits keratinocyte proliferation and causes cell cycle arrest through increased intracellular calcium [77]. A 2A , another adenosine receptor, little expressed in resting keratinocytes, is upregulated in psoriatic epidermis [77], and by cytokines such as Il-1 and TNF, indicating that adenosine signaling shifts to this receptor under inflammatory conditions. This leads to cell proliferation via p38 signaling [77].…”

“…A 2A , another adenosine receptor, little expressed in resting keratinocytes, is upregulated in psoriatic epidermis [77], and by cytokines such as Il-1 and TNF, indicating that adenosine signaling shifts to this receptor under inflammatory conditions. This leads to cell proliferation via p38 signaling [77]. Since adenosine reduced cell numbers, the expression of the adenosine receptor A 2B rather than A 2A prevailed in the present experiments.…”

“…Intriguingly, if the expression of A 2A dominates, which can occur in stressed tissues [77] or malignancies [78], activation of p38 signaling could increase the expression of HAS2, as observed in keratinocytes [35,39], and actually lead to increased hyaluronan production.…”

“…However, adenosine can also signal via receptor-independent mechanisms such as through adenosine uptake, followed by conversion to AMP with its intracellular signaling functions [79], or by influencing membrane phosphatase activity [77]. The delayed responses, including the upregulation of HAS1 after 4-6 h and the secondary waves of HAS2 and HAS3 activation after 24 h, are likely processes secondary to the initial signals induced by the nucleotides.…”

“…However, it stimulates motility in inflammatory cells and in breast cancer cells via autocrine activation of the A 3 receptor, but inhibits cell migration when added exogenously ( [93], and references therein). The expression of this receptor is low in keratinocytes [77], perhaps explaining why no change in migration was found. Actually, there was a tendency towards reduced migration at the early phase, coincidentally with the inhibition of HAS2 expression.…”