Interleukin‐4 and Dexamethasone Counterregulate Extracellular Matrix Remodelling and Phagocytosis in Type‐2 Macrophages

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Abstract
Alternatively activated macrophages (Mφ2) are induced by Th2 cytokines and by glucocorticoids (GC), and can be distinguished from classically activated effector macrophages (Mφ1) on the basis of their anti‐inflammatory properties. In addition, Mφ2 are involved in Th2/Th1 skewing, enhance antigen uptake and processing and support tissue remodelling and healing. In order to elucidate the heterogeneity of Mφ2 population systematically, we analysed a number of genes involved in extracellular matrix (ECM) remodelling, inflammation and phagocytosis in Mφ2 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 Mφ2‐associated TG, was synergistically regulated by IL‐4 and GC. Enzyme‐linked immunosorbent assay analysis revealed that the production of Mφ2‐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 Mφ with IL‐4 and GC regulate antagonistically the expression of ECM remodelling‐related molecules and phagocytosis of opsonized and non‐opsonized particles.