Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes

Recent studies demonstrate in vivo and in vitro cytokine dysregulation in C F epithelial cells. To see if these abnormalities may be generalized to oth er cells expressing cystic fibrosis transmembrane conductance regulator (CF TR) but not directly exposed to local inflammation, we studied mRNA transcr iption, intracellular protein production and extracellular secretion of IL- 2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma) from freshly isolated blood mononuclear and CD4(+) T cells from CF patients and controls. Cells were activated by phorbol myristate acetate (PMA) and anti-CD3, PMA-ionomyc in, or lipopolysaccharide (LPS) and assessed for cytokine mRNA transcriptio n by semiquantitative reverse transcriptase-polymerase chain reaction, intr acellular protein production by flow cytometry, and secretion by supernatan t ELISA. Cytokine expression was highly stimulus-dependent. CF cells showed higher IL-10 transcription than control cells after maximal activation by LPS (P = 0.01); despite this, cytokine production and secretion were equiva lent to controls. CF cells showed lower cellular IL-IO production after PMA -anti-CD3 activation (P = 0.002). CF cells secreted less lFN-gamma than con trol cells after maximal activation by PMA-anti-CD3 (1836 +/- 273 pg/ml ver sus 9635 +/- 3437 pg/ml, P = 0.04). IL-2, IL-4 and IL-5 regulation was simi lar to controls. We conclude that CF mononuclear cells show selective cytok ine dysregulation after maximal activation, namely reduced lFN-gamma secret ion and increased IL-IO mRNA without increased production or secretion. The se findings extend defects described in respiratory epithelial cells to cir culating immunoregulatory cells, suggesting a link between CF genotype and cytokine dysregulation.