One of the oldest and most preserved of the The systemic response to tissue injury caused by infection or trauma is the well-recognized series of humoral and cellular reactions known collectively as the acute inflammatory response. This response consists of leukocytosis, fever, increased vascular permeability, alterations in plasma metal and steroid concentrations, along with increased levels of liver-derived plasma proteins (1, 2). The liver responds early to trauma with increased uptake of amino acids as well as iron and zinc. In addition, there is a marked increase in the hepatocyte mRNA for a number of plasma proteins. These include a1-acid glycoprotein, a1-proteinase inhibitor (a1-antitrypsin), a1-antichymotrypsin, haptoglobin, hemopexin, and fibrinogen in most species, along with C-reactive protein, C3, and factor B complement components and serum amyloid A protein in humans, and a2-macroglobulin and a1-cysteine proteinase inhibitor (major acute phase protein) in the rat. The change in mRNA is followed within a few hours by an increase in the secretion of the proteins by the liver and increased plasma levels of these acute phase reactants within 24 hr. The acute phase reaction has been the subject of recent reviews (3, 4). The identity of the putative hormone-like messenger, released at the site of injury and traveling to the liver, as suggested by Koj (5), has received considerable attention of late. It now appears certain that most nonhepatic acute phase reactions can be attributed to the release of a family of polypeptides, originally described as leukocyte endogenous mediator or endogenous pyrogen (6, 7), now known as interleukin 1 (IL-1), and a second series of peptides known as tumor necrosis factor (TNF). These polypeptide cytokines interact with a broad spectrum of target tissues and would appear to control major components of the inflammatory response (8, 9).Using in vitro hepatocyte cell cultures of primary rat hepatocytes and rat and human hepatoma cells, we and others have shown that IL-1 and TNF induce only a restricted acute phase response in vitro (10-15). The full hepatic acute phase protein response is controlled by a separate cytokine, originally described as fibrinogen-stimulating factor (16) and more recently known as hepatocyte-stimulating factor (HSF) (17-19). Human monocyte-derived HSF is a polypeptide released by activated monocytes and macrophages, which elutes from molecular sieve chromatography as a 25-to 30-kDa protein and has an isoelectric point of 5 (18,20,21). Human keratinocytes release HSFs with similar activities on hepatocytes (22). The cytokines IL-1 and TNF control only a subset of the acute phase protein genes (including a1-acid glycoprotein, C3, and haptoglobin) in human and rat hepatocytes while monocytic as well as keratinocytic HSF controls the expression of the remaining acute phase proteins (including the antiproteinases and fibrinogen) and has a lesser but still significant effect on the first subset of acute phase proteins (refs. 12 and 23; H.B., C.R.,...

Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein, and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high-throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL-6 family, as a major coupling factor produced by activated circulating CD14 1 or bone marrow CD11b 1 monocytes/macrophages that induce osteoblast differentiation and matrix mineralization from human mesenchymal stem cells while inhibiting adipogenesis. Upon activation of toll-like receptors (TLRs) by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase-2 and prostaglandin-E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR, or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of CCAAT-enhancer-binding protein d, Cbfa1, and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines have also a potent role in bone formation induced by monocytes/macrophages and activation of TLRs: IL-6 and leukemia inhibitory factor. We propose that during bone inflammation, infection, or injury, the IL-6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies. STEM CELLS 2012;30:762-772 Disclosure of potential conflicts of interest is found at the end of this article.

Bioreactive substances in the plasma supernatant of the platelet product cause most febrile reactions associated with platelet transfusions. Removing the plasma supernatant before transfusion can minimize or prevent these reactions.

Oncostatin M is a secreted cytokine involved in homeostasis and in diseases involving chronic inflammation. It is a member of the gp130 family of cytokines that have pleiotropic functions in differentiation, cell proliferation, and hematopoetic, immunologic, and inflammatory networks. However, Oncostatin M also has activities novel to mediators of this cytokine family and others and may have fundamental roles in mechanisms of inflammation in pathology. Studies have explored Oncostatin M functions in cancer, bone metabolism, liver regeneration, and conditions with chronic inflammation including rheumatoid arthritis, lung and skin inflammatory disease, atherosclerosis, and cardiovascular disease. This paper will review Oncostatin M biology in a historical fashion and focus on its unique activities, in vitro and in vivo, that differentiate it from other cytokines and inspire further study or consideration in therapeutic approaches.

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