Regulated Extracellular Nucleotide Metabolism and Function at the Mucosa - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 121

Chapter 8
Regulated Extracellular Nucleotide Metabolism
and Function at the Mucosa

Christopher F. MacManus, Holger K. Eltzschig, and Sean P. Colgan

Abstract Within mucosal tissues, regulation of nucleotide metabolism may be
directed at various physiological/pathophysiological levels by myriad cell types.
Adenosine (Ado) can regulate a number of processes at the mucosa, e.g. damp-
ening of the inflammatory response and resultant tissue protection. Ado receptors
are widely expressed on a variety of organs and cell types and have been demon-
strated to be central to the modulation of inflammation. In many instances, local Ado
levels are dictated by extracellular sources of adenine nucleotides. Activated neu-
trophils and platelet degranulation are two such important sources of ATP and ADP.
Sequential phosphohydrolysis of adenine nucleotides by CD39 and CD73 results in
the conversion of ATP and ADP to AMP, and the subsequent conversion of AMP to
Ado, whereby signaling through Ado receptors can elicit effects such as increase
in endothelial barrier function, increase in epithelial electrogenic Cl - secretion
and water transport. Further regulation of Ado signaling has been observed under
hypoxic conditions, due to hypoxia-inducible factor-1 (HIF-1)-regulated expression
of A2BR and CD73, whereby additional SP-1 transcription factor activity has been
identified as being required for hypoxic induction of CD39 expression in endothe-
lial cells. Here we describe the different levels of regulation of adenine nucleotide
metabolism and the resultant functional cell-cell signaling at the mucosa.

8.1 Nucleotide Metabolism at the Mucosa

The mucosal surfaces (tissues or organs lined by an epithelium) represent a com-
plex environment wherein a diverse array of cell types may interact, including
endothelia, epithelia, hematological cells and stromal cells. It is therefore impor-
tant to understand the complexity of signaling networks that exist to orchestrate
physiological and pathophysiological events within these tissues. Nucleotides and

B C.F. MacManus ( )

Mucosal Inflammation Program, 12700 E. 19th Ave, Aurora, CO 80045, USA
e-mail: [e-mail]
The authors declare no financial interests in any of the work submitted here.