Elevated IL-10 inhibits GM-CSF synthesis in pulmonary alveolar proteinosis

Pulmonary alceolar proteinosis (PAP) is an autoimmune lung disease characterized by accumulation of surfactant material within the lung. Autoantibodies to GM-CSF as well as high levels of IL-10 are also found in the lungs in PAP. Previous studies suggest that treatment with recombinant GM-CSF is beneficial for patients with low levels of GM-CSF antibodies. The role of IL-10 in PAP, however, is unknown and the hypothesis that IL-10 may affect PAP GM-CSF synthesis has not been addressed. The current findings show that GM-CSF secretion is significantly compromised in PAP bronchoalveolar lavage (BAL) cells compared to controls, but surprisingly, GM-CSF mRNA levels are elevated. In contrast, IL-10 protein and mRNA levels are both highly elevated in PAP. In vitro analysis of GM-CSF regulation indicates that both secretion and mRNA levels are sharply reduced by IL-10 and increased by anti-IL-10 antibody. The phenomenon of elevated GM-CSF mRNA in BAL cells appears not to be due to lack of negative feedback by GM-CSF protein. Results suggest that in PAP, GM-CSF synthesis is deficient and associated with negative regulation by IL-10. Furthermore, IL-10 gene expression becomes even more elevated in patients who do not respond to recombinant GM-CSF therapy and have high anti-GM-CSF titers. Based on these observations, we hypothesize that IL-10 may be an indicator of PAP clinical response to GM-CSF therapy.