Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 83, Issue 6, Pages 1323-1333Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.1107782
Keywords
fibrosis; inflammation; monocytes; pentraxin; serum amyloid P
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL083029] Funding Source: NIH RePORTER
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [R01 HL083029-02, R01 HL083029, HL 083029] Funding Source: Medline
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CD14+ peripheral blood monocytes can differentiate into fibroblast-like cells called fibrocytes, which are associated with and are at least partially responsible for wound healing and fibrosis in multiple organ systems. Signals regulating fibrocyte differentiation are poorly understood. In this study, we find that when added to human PBMCs cultured in serum-free medium, the profibrotic cytokines IL-4 and IL-13 promote fibrocyte differentiation without inducing fibrocyte or fibrocyte precursor proliferation. We also find that the potent, antifibrotic cytokines IFN-gamma and IL-12 inhibit fibrocyte differentiation. In our culture system, IL-1 beta , IL-3, IL-6, IL-7, IL-16, GM-CSF, M-CSF, fetal liver tyrosine kinase 3, insulin growth factor 1, vascular endothelial growth factor, and TNF-alpha had no significant effect on fibrocyte differentiation. IL-4, IL-13, and IFN-gamma act directly on monocytes to regulate fibrocyte differentiation, and IL- 12 acts indirectly, possibly through CD16-positive NK cells. We previously identified the plasma protein serum amyloid P (SAP) as a potent inhibitor of fibrocyte differentiation. When added together, the fibrocyte-inhibitory activity of SAP dominates the profibrocyte activities of IL-4 and IL-13. The profibrocyte activities of IL- 4 and IL-13 and the fibrocyte-inhibitory activities of IFN-gamma and IL-12 counteract each other in a concentration-dependent manner. These results indicate that the complex mix of cytokines and plasma proteins present in inflammatory lesions, wounds, and fibrosis will influence fibrocyte differentiation.
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