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.
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-5038, USA. thomasm@ccf.org
Mary Jane
MJ
Thomassen
Baisakhi
B
Raychaudhuri
Tracey L
TL
Bonfield
Anagha
A
Malur
Susamma
S
Abraham
Barbara P
BP
Barna
Mani S
MS
Kavuru
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011649:Pulmonary Alveolar Proteinosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification; D011994:Recombinant Proteins
D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor