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_2AR) 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<sub>2A</sub>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_2AR 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<sub>2A</sub>R up-regulation offers interesting clues regarding the course of sepsis.—Kreth, S., Ledderose, C., Kaufmann, I., Groeger, G., Thiel, M. Differential expression of 5`-UTR splice variants of the adenosine A_2AR gene in human granulocytes: identification, characterization, and functional impact on activation.