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

Abstract

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-1beta, 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.

Leukocyte composition of human breast cancer

“…Although used successfully in multiple studies to relate TAM infiltration with clinically relevant outcomes, our results indicate that CD68 alone cannot accurately evaluate macrophage presence in human breast tissue given that multiple stromal cells express it and that a subset of these are CSF1R-and CD45-negative. We observed that the nonleukocytic CD68 + cells were predominantly located within tumor stroma and, thus, based on this localization and morphology, we speculate that CSF1R − CD68 + cells likely reflect tumor-associated fibroblasts or monocyte-derived fibrocytes in agreement with other reports (31,32,(49)(50)(51)(52). Our findings do not invalidate CD68 as a clinically relevant marker and, importantly, CSF1-response gene signatures have been identified in breast adenocarcinomas that are predictive of recurrence risk and metastasis (53,54).…”

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

“…1A). As previously observed (31), the presence of TNF-α alone did not significantly affect fibrocyte differentiation (Fig. 1A).…”

“…To test the hypothesis that activated fibroblasts might secrete soluble factors that promote fibrocyte differentiation, we added conditioned medium from human fibroblasts incubated with TNF-α (FCM+TNF-α) to human peripheral blood mononuclear cells (PBMC) in conditions where some of the monocytes in the PBMC would normally differentiate into fibrocytes. We used TNF-α as the stimulus, as other profibrotic cytokines such as IL-4, IL-13, and TGF-β act directly on monocytes to regulate fibrocyte differentiation (31). TNF-α is produced by monocytes, macrophages, and fibrocytes, serum TNF-α levels are increased in fibrosis patients, and TNF-α induces fibrosis in animal models (32)(33)(34)(35)(36).…”

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

“…Fibrocytes were harvested and cultured as previously described (24,25). Briefly, peripheral blood mononuclear cells (PBMCs) were isolated from murine or human blood by using Lymphoprep™ (Progen Biotechnik).…”