Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages

Alternatively activated macrophages (Mphi2) are induced by Th2 cytokines and by glucocorticoids (GC), and can be distinguished from classically activated effector macrophages (Mphi1) on the basis of their anti-inflammatory properties. In addition, Mphi2 are involved in Th2/Th1 skewing, enhance antigen uptake and processing and support tissue remodelling and healing. In order to elucidate the heterogeneity of Mphi2 population systematically, we analysed a number of genes involved in extracellular matrix (ECM) remodelling, inflammation and phagocytosis in Mphi2 populations generated with interleukin-4 (IL-4) or GC. Using real-time polymerase chain reaction, we demonstrated that the ECM component, tenascin-C, is stimulated by IL-4, whereas it is suppressed by dexamethasone. The ECM remodelling enzymes - MMP-1 and MMP-12 - and tissue transglutaminase (TG) showed a similar regulation pattern. FXIIIa, another putative Mphi2-associated TG, was synergistically regulated by IL-4 and GC. Enzyme-linked immunosorbent assay analysis revealed that the production of Mphi2-associated chemokines, AMAC-1, MCP-4 or TARC, was induced by IL-4 and was modulated by GC. Phagocytosis of opsonized and non-opsonized particles was stimulated by GC, whereas IL-4 had only a modulatory effect, what may be partially explained by the expression pattern of hMARCO, a scavenger receptor for non-opsonized particles, that was strongly and selectively induced by GC. In conclusion, stimulation of Mphi with IL-4 and GC regulate antagonistically the expression of ECM remodelling-related molecules and phagocytosis of opsonized and non-opsonized particles.