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.
Gratchev
A
A
Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany. alexei.gratchev@haut.ma.uni-heidelberg.de
Kzhyshkowska
J
J
Utikal
J
J
Goerdt
S
S
D001483:Base Sequence; D018925:Chemokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D051116:Receptors, Scavenger; D019063:Tenascin / Q000235:genetics; D011503:Transglutaminases / Q000235:genetics
D018925:Chemokines; C490460:MARCO protein, human; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D019063:Tenascin; D015847:Interleukin-4; D003907:Dexamethasone; D011503:Transglutaminases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1