This supports the concept of a dynamic equilibrium between inflammation induction and suppression in order to avoid excessive tissue damage. Clearly, gram-positive bacteria are also able to directly induce SOCS and NALP2 gene transcription but the actual pathway of signal transduction here must be attributed either only to TLR9 or another pathogen-recognition receptor, most likely TLR2 [25]. The microarray results also point to a novel and obviously important function of stimulated monocytes in angiogenesis and modulation of the peripheral vascular tonus. We observed the upregulation of transcription of the find more strong vasoactive mediators END1, VEGF and F3. Endothelin 1 (END1) is a potent
vasoconstrictor and angiogenic peptide. Its expression has been attributed to damaged vascular endothelium, mast cells or macrophages in atherosclerotic lesions and thus it appears to be also a feature of stimulated monocytes in response to infection. The potential effect of
endothelin induction also CT99021 mouse selleck inhibitor correlates with the upregulation of VEGF by all three pathogens. VEGF (vascular epithelium growth factor) is a major inducer of vascularization and angiogenesis [26, 27]. In keeping with this observation we find that F3 (coagulation factor III thromboplastin tissue factor) is also overexpressed. Blood coagulation together with vasoconstriction ensures wound closing and prevents blood loss, but also prevents the invasion and spread of pathogens at the site of injury. Osteopontin (also upregulated) protects the endothelial cells against apoptosis and induces cell survival and proliferation. It also promotes migration of macrophages and dendritic cells to the site of inflammation
and induces IL-12 secretion while down regulating the inducible nitric oxide synthase CYTH4 (iNOS) expression and the NO production by macrophages [19]. Our findings suggest that peripheral monocytes may have a very distinct role in processes of wound healing and the maintenance of environmental barriers when stimulated by bacterial pathogens. Interestingly some of the genes found upregulated in the monocytes were reported to have been regulated in endothelial cells upon treatment with VEGF: Egr3, Dusp4 [28] thus suggesting autocrine effects of VEGF (for LM and SA). Also the upregulation of VEGF in this study was two-fold for every single pathogen unlike the rest of upregulated cytokines and chemokines, which were usually more strongly upregulated by LM and SA. This may be interpreted as a sign for a very tight regulation of this growth factor, since another strong effect of VEGF is endothelium permeabilization, which may cause undesired exudate formation. Another interesting characteristic of the common response was the upregulation of genes, known to counteract apoptotic signals and the absence of significant changes in the transcription of proapoptotic mediators.