BACKGROUND AND PURPOSE: Human monocyte-derived M1 macrophages develop in relation to growth factors, bacterial products, and cytokines in a local micro-environment. M1 macrophages produce pro-inflammatory mediators, in particular, oncostatin M (OSM), which is secreted from the cells in response to the active complement component C5a. As C5a also releases histamine from human mast cells and shows immune modulatory functions similar to histamine in regulating expression of the IL-12 cytokine family, we investigated the effects of histamine on OSM expression in human M1 macrophages. EXPERIMENTAL APPROACH: Cytokine expression was analysed by real-time quantitative PCR and elisa techniques. Normal human epidermal keratinocytes were stimulated with supernatants from activated M1 macrophages, and phosphorylation of STAT3 was assessed by flow cytometry. KEY RESULTS: OSM mRNA expression was highly up-regulated by histamine and agonists targeting the histamine H1 H2 , and H4 receptors in human M1 macrophages and by C5a, which was used as control stimulus. Protein levels of OSM and IL-6 were up-regulated by histamine. Supernatants from histamine-stimulated, fully differentiated M1 macrophages were able to phosphorylate STAT3 in normal human epidermal keratinocytes. CONCLUSIONS AND IMPLICATIONS: The up-regulation of OSM expression in response to histamine and C5a shown in this study provides further evidence that histamine and C5a, acting through their GPCRs, have almost equal functional effects in cells of the monocyte lineage. Both mediators OSM and IL-6 have the capability to activate human keratinocytes. This effect may have an influence on the course of inflammatory skin diseases. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.