A more recent version of this article appeared on June 1, 2008

Published online before print March 10, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1107782

Received for publication November 20, 2007.
Revised January 28, 2008.
Accepted for publication February 12, 2008.

Article

Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation

Diane D. Shao , Rahul Suresh , Varsha Vakil , Richard H. Gomer , and Darrell Pilling ^@

Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, USA

^@ To whom correspondence should be addressed. E-mail: dpilling{at}rice.edu.

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- and IL-12 inhibit fibrocyte differentiation. In our culture system, IL-1, 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- had no significant effect on fibrocyte differentiation. IL-4, IL-13, and IFN- 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- 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.

Key Words: fibrosis • inflammation • monocytes • pentraxin • serum amyloid P

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