Differential expression of 5′-UTR splice variants of the adenosine A2A receptor gene in human granulocytes:: identification, characterization, and functional impact on activation

A key step in the pathogenesis of sepsis is the excessive and uncontrolled activation of polymorphonuclear neutrophils (PMNs). An inflammation-controlling function of adenosine receptors has been presumed; however, their role in PMN of sepsis patients is poorly defined. We investigated the expression of adenosine receptors in resting and lipopolysaccharide (LPS)-activated human PMNs, and in PMNs of sepsis patients. Our studies revealed that native human PMNs express almost equal distributions of all four adenosine receptor subtype transcripts, whereas exclusively the A(2A) receptor (A(2A)R) was up-regulated in LPS-stimulated PMNs and PMNs of sepsis patients. As a possible mechanism, we identified and fully characterized eight 5'-untranslated region (UTR) splice variants of the A(2A)R gene resulting from alternative transcription and/or splicing of five noncoding exons. We report a differential, activation state-specific expression of 5'-UTR variants within the same cell type, indicating a new mechanism to modulate gene expression: In resting human PMNs, mainly A(2A)R transcripts with long 5'-UTRs are expressed, whereas in stimulated PMNs and PMNs of septic patients, short 5'-UTRs predominate. Transcripts with short 5'-UTRs are more efficiently translated into protein. The correlation between changes of transcript patterns and A(2A)R up-regulation offers interesting clues regarding the course of sepsis.