Incubation of bone marrow macrophages with lipopolysaccharide (LPS) or interferon gamma (IFN gamma) blocks macrophage proliferation. LPS treatment or M-CSF withdrawal arrests the cell cycle at early G1 and induces apoptosis. Treatment of macrophages with IFN gamma stops the cell cycle later, at the G1/S boundary, induces p21Waf1, and does not induce apoptosis. Moreover, pretreatment of macrophages with IFN gamma protects from apoptosis induced by several stimuli. Inhibition of p21Waf1 with antisense oligonucleotides or using KO mice shows that the induction of p21Waf1 by IFN gamma mediates this protection. Thus, IFN gamma makes macrophages unresponsive to apoptotic stimuli by inducing p21Waf1 and arresting the cell cycle at the G1/S boundary. Therefore, the cells of the innate immune system could only survive while they were functionally active.

Decorin is a small proteoglycan that is ubiquitous in the extracellular matrix of mammalian tissues. It has been extensively demonstrated that decorin inhibits tumor cell growth; however, no data have been reported on the effects of decorin in normal cells. Using nontransformed macrophages from bone marrow, results of this study showed that decorin inhibits macrophage colony-stimulating factor (M-CSF)-dependent proliferation by inducing blockage at the G 1 phase of the cell cycle without affecting cell viability. In addition, decorin rescues macrophages from the induction of apoptosis after growth factor withdrawal. Decorin induces the expression of the cdk inhibitors p21 Waf1 and p27 Kip1 . Using macrophages from mice where these genes have been disrupted, inhibition of proliferation mediated by decorin is related to p27 Kip1 expression, whereas p21 Waf1 expression is necessary to protect macrophages from apoptosis. Decorin also inhibits M-CSF-dependent expression of MKP-1 and extends the kinetics of ERK activity, which is characteristic when macrophages become activated instead of proliferating. The effect of decorin on macrophages is not due to its interaction with epidermal growth factor or interferon-␥ receptors. Furthermore, decorin increases macrophage adhesion to the extracellular matrix, and this may be partially responsible for the expression of p27 Kip1 IntroductionStimulated monocytes and macrophages secrete a diverse set of mediators that influence cellular immune functions and inflammation. These mediators include proinflammatory and anti-inflammatory cytokines, prostaglandins, leukotrienes, and reactive oxygen metabolites. 1 At the inflammatory sites, proteoglycans are both secreted by activated mononuclear leukocytes and released as a result of extracellular matrix (ECM) degradation. Thus, proteoglycans, which are major constituents of the ECM, are another class of molecules produced by monocytes and macrophages 2,3 that are potential modulators of the immune response.Decorin belongs to a family of small leucine-rich proteoglycans 4,5 and is found in the ECM of several of tissues such as skin, 6,7 cartilage, 8,9 and bone. 10 The biologic importance of these molecules is unclear. In vitro binding studies have shown that some of them interact with several types of collagen 11,12 and act as important regulators of collagen fibrillogenesis. In support of this hypothesis, a decorin-deficient mouse was found to have fragile skin with an abnormal organization of collagen fibers. 13 Decorin may also affect the production of other ECM components by regulating the activity of transforming growth factor-␤ (TGF-␤). 14,15 Additionally, decorin can modulate the interactions of matrix molecules (eg, fibronectin) with cells. [16][17][18] These observations suggest that decorin and perhaps other proteoglycans regulate the production and assembly of the ECM at several levels and hence the remodeling of connective tissue.Different observations have revealed that decorin is involved in the control of cell prolif...

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Several cytokines or growth factors induce macrophages to proliferate, become activated, differentiate, or die through apoptosis. Like the major macrophage activator IFN-γ, the extracellular matrix protein decorin inhibits proliferation and protects macrophages from the induction of apoptosis. Decorin enhances the IFN-γ-induced expression of the IAα and IAβ MHC class II genes. Moreover, it increases the IFN-γ- or LPS-induced expression of inducible NO synthase, TNF-α, IL-1β, and IL-6 genes and the secretion of these cytokines. Using a number of extracellular matrix proteins, we found a negative correlation between adhesion and proliferation. However, the effects of decorin on macrophage activation do not seem to be mediated through its effect on adhesion or proliferation. Instead, this proteoglycan abolishes the binding of TGF-β to macrophages, as shown by Scatchard analysis of 125I-labeled TGF-β, which, in the absence of decorin, showed a Kd of 0.11 ± 0.03 nM and ∼5000 receptors/cell. This was confirmed when we treated macrophages with Abs to block the endogenously produced TGF-β, which enhanced macrophage activation in a way similar to decorin. The increase in activation mediated by decorin demonstrates that macrophages are under negative regulation that can be reversed by proteins of the extracellular matrix.