PURPOSE: Procalcitonin (PCT) is an acute-phase protein and widely used marker for diagnosing bacterial infection and sepsis, but its physiological role remains incompletely defined. Interleukin-1beta (IL-1beta) is a critical mediator of the immune response to infection, whose excessive release can drive remote organ injury and dysfunction. Its secretion is therefore tightly controlled. Because other acute-phase proteins have been shown to regulate IL-1beta secretion, we investigated whether PCT exerts a similar immunomodulatory effect and whether this influences sepsis severity, particularly in Gram-negative urosepsis. METHODS: Primary human mononuclear leukocytes were stimulated to induce IL-1beta release in the presence or absence of increasing PCT concentrations. In parallel, peak PCT levels, infection source, and causative pathogen were analyzed retrospectively in uroseptic patients in comparison to other septic sources, and related to Sepsis-related Organ Failure Assessment (SOFA) scores and serum lactate concentrations. RESULTS: PCT significantly inhibited IL-1beta secretion from primary mononuclear leukocytes across the 2.5-75 microg/L concentration range. Clinically, the highest PCT peaks occurred in patients with Gram-negative urosepsis. Among these, those with peak PCT values within 2.5-75 microg/L had significantly lower SOFA scores and lactate levels-established indicators of sepsis severity and prognosis-compared with patients outside this range. CONCLUSION: Within a defined concentration range, PCT down-regulates IL-1beta secretion and is associated with reduced markers of disease severity in Gram-negative urosepsis, compared to other sepsis entities. These findings suggest that pronounced PCT elevations in this setting may represent a protective host response rather than a worse prognosis, pointing to a novel immunomodulatory role of PCT in urosepsis that warrants further investigation. DRKS00037950, retrospectively registered on 22 September 2025.
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