Monocytes and macrophages are important effectors and regulators of inflammation, and both their differentiation and activation are regulated strictly in response to environmental cues. Angiopoietin-like protein 2 (Angpt12) is a multifaceted protein, displaying many physiological and pathological functions in inflammation, angiogenesis, hematopoiesis, and tumor development. Although recent studies implicate Angpt12 in chronic inflammation, the mechanisms of inflammation caused by Angpt12 remain unclear. The purpose of the present study was to elucidate the role of Angpt12 in inflammation by understanding the effects of Angpt12 on monocytes/macrophages. We showed that Angptl2 directly activates resident murine peritoneal monocytes and macrophages and induces a drastic upregulation of the transcription of several inflammatory genes including nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, and several proinflammatory cytokine genes such as interleukin (IL)-1 beta, IL-6, TNF alpha, and CSF2, along with activation of ERK, JNK, p38, and nuclear factor kappa B signaling pathways. Concordantly, proinflammatory cytokines IL-1 beta, IL-6, TNF alpha, and GM-CSF, were rapidly elevated from murine peritoneal monocytes and macrophages. These results demonstrate a novel role for Angpt12 in inflammation via the direct activation of peritoneal monocytes and macrophages. (C) 2015 Elsevier Inc. All rights reserved.