Thus the activation of LXR may play a role in resolution of inflammation processes

e M2 marker Arg1 in comparison to BMDM. The trigger for this activation is unknown. Our explant studies showed differences in protein levels or expression of the Th2 cytokines IL-4 or -13 in SRuPA+/0 versus NTG hearts and our previous studies did not detect increased numbers of lymphocytes in hearts of SR-uPA+/0 mice. However, we did confirm another report that il13 is expressed in the mouse heart and may therefore contribute to fibrosis. Because SR-uPA+/0 macrophages are sensitized to IL-4 stimulation, it is possible that baseline cardiac levels on IL-13 are sufficient to activate SR-uPA+/0 macrophages to an M2 phenotype after migration. On the other hand, Dupasquier, et al noted that in the course of monocytes migrating to the skin to become Langerhans cells, M2 activation occurred independent of IL-4/13 signaling. Crossing the SR-uPA+/ 0 mouse with the Il4ra knockout mouse would help resolve this mechanism, however, as the Il4ra2/2 mouse strain is on a different background, such experiments would require extensive back crossing and breeding outside of the scope of this report. Alternatively, the heart may be particularly sensitive to SRuPA+/0 macrophages. In our previous work we noted that fibrosis is limited to the heart in SR-uPA+/0 mice, consistent with other studies showing an anti-fibrotic or neutral effect of excess uPA in other organs. Our in vitro data support that the ability of SR-uPA+/0 macrophages to increase collagen production is limited to cardiac fibroblasts. Expression of Col1a1 in response to conditioned media from SR-uPA+/0 macrophages is robustly upregulated in cardiac fibroblasts but not the NIH3T3 embryonic fibroblast cell line. This finding may explain why TAM’s with TG 02 site similar gene expression profiles rarely promote fibrosis in malignant tumors. Developmental studies support that tissues contain stem cells that contribute both to populations of specialized cells such as cardiomyocytes and “supportive”cells such as fibroblasts and vascular smooth muscle cells. These developmental differences in fibroblast populations may lead to differential sensitivity to pathologic stimuli in adulthood. Alternatively, quiescent fibroblast precursors may be the target of SRuPA+/0 macrophages. Further studies to elucidate the role of these precursor populations in uPA-induced cardiac fibrosis are planned but outside the scope of this report. The precise mechanisms by which SR-uPA+/0 macrophages induce collagen deposition remain unknown. TGF-b1 is reported as the classic M2 pro-fibrotic factor, due to its ability to directly stimulate fibroblast activation and expression of Col1a1. We have previously reported that neither TGF-b1 protein nor signaling is increased in hearts of SR-uPA+/0 mice prior to the onset of fibrosis. Here we show that isolated SR-uPA+/ 0 macrophages do not express excess TGF-b1. In addition, array studies did not indicate increases in downstream 1700309 products of TGFb1 or increases in classic TGF-b1 transcription pathways. Although these array studies cannot completely rule out activation of all TGF-b1 signaling pathways in SR-uPA+/0 mice, our cumulative data support that classical signaling 2837278 by TGF- b1 is not associated with uPA-induced cardiac fibrosis. Because arginase activity was upregulated in both isolated macrophages and hearts of SR-uPA mice, we hypothesized that arginase is a regulator of cardiac fibrosis in SR-uPA mice. Although there were no increases in Arg1 protein in SR-uPA+/0 macrophages, arginase act

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