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Alternative activation of macrophages, induced by Th2 cytokines and glucocorticoids, is essential for the proper functioning of anti-inflammatory immune reactions. To this end, alternatively activated macrophages (aaMΦ) express a not yet fully unravelled set of genes including cytokines such as alternative macrophage activation-associated CC-chemokine (AMAC)-1 and pattern recognition molecules such as the scavenger receptor CD163. In order to further characterize the molecular repertoire of aaMΦ, differential gene expression was analyzed by combining subtractive suppression cloning and differential hybridization. We show here that aaMΦ induced by interleukin (IL)-4 overexpress the prototype extracellular matrix (ECM) protein fibronectin on the mRNA and protein level. This overall increase is accompanied by a shift in fibronectin splice variants from an embryonic to a mature pattern. In addition, the expression of another ECM protein, βIG-H3, is also upregulated by IL-4 in aaMΦ. In contrast to IL-4 and in line with its inhibitory effect on wound healing, dexamethasone exerts a strongly suppressive effect on fibronectin and βIG-H3 expression. In conclusion, overexpression of ECM proteins induced by IL-4 in macrophages suggests that aaMΦ may be involved in ECM deposition and tissue remodelling during the healing phase of acute inflammatory reactions and in chronic inflammatory diseases.