Extravascular fibrin deposition is an early and persistent hallmark of inflammatory responses. Fibrin is generated from plasma-derived fibrinogen, which escapes the vasculature in response to endothelial cell retraction at sites of inflammation. Our ongoing efforts to define the physiologic functions of extravasated fibrin(ogen) have led to the discovery, reported here, that fibrinogen stimulates macrophage chemokine secretion. Differential mRNA expression analysis and RNase protection assays revealed that macrophage inflammatory protein-1α (MIP-1α), MIP-1β, MIP-2, and monocyte chemoattractant protein-1 are fibrinogen inducible in the RAW264.7 mouse macrophage-like cell line, and ELISA confirmed that both RAW264.7 cells and primary murine thioglycolate-elicited peritoneal macrophages up-regulate the secretion of monocyte chemoattractant protein-1 >100-fold upon exposure to fibrinogen. Human U937 and THP-1 precursor-1 (THP-1) monocytic cell lines also secreted chemokines in response to fibrinogen, upon activation with IFN-γ and differentiation with vitamin D3, respectively. LPS contamination could not account for our observations, as fibrinogen-induced chemokine secretion was sensitive to heat denaturation and was unaffected by the pharmacologic LPS antagonist polymyxin B. Nevertheless, fibrinogen- and LPS-induced chemokine secretion both apparently required expression of functional Toll-like receptor 4, as each was diminished in macrophages derived from C3H/HeJ mice. Thus, innate responses to fibrinogen and bacterial endotoxin may converge at the evolutionarily conserved Toll-like recognition molecules. Our data suggest that extravascular fibrin(ogen) induces macrophage chemokine expression, thereby promoting immune surveillance at sites of inflammation.

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein–coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3−/−) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3−/− allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR+/+ mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

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This nationally representative telephone (wire-line and cell phone) survey explores Americans' opinions about behavioral targeting by marketers, a controversial issue currently before government policymakers. Behavioral targeting involves two types of activities: following users' actions and then tailoring advertisements for the users based on those actions. While privacy advocates have lambasted behavioral targeting for tracking and labeling people in ways they do not know or understand, marketers have defended the practice by insisting it gives Americans what they want: advertisements and other forms of content that are as relevant to their lives as possible. Contrary to what many marketers claim, most adult Americans (66%) do not want marketers to tailor advertisements to their interests. Moreover, when Americans are informed of three common ways that marketers gather data about people in order to tailor ads, even higher percentagesbetween 73% and 86% -say they would not want such advertising. Even among young adults, whom advertisers often portray as caring little about information privacy, more than half (55%) of 18-24 years-old do not want tailored advertising. And contrary to consistent assertions of marketers, young adults have as strong an aversion to being followed across websites and offline (for example, in stores) as do older adults. This survey finds that Americans want openness with marketers. If marketers want to continue to use various forms of behavioral targeting in their interactions with Americans, they must work with policymakers to open up the process so that individuals can learn exactly how their information is being collected and used, and then exercise control over their data. We offer specific proposals in this direction. An overarching one is for marketers to implement a regime of information respect toward the public rather than to treat them as objects from which they can take information in order to optimally persuade them. A N D T H R E E A C T I V I T I E S T H A T E N A B L E I T Joseph Turow OverviewContrary to what many marketers claim, most adult Americans (66%) do not want marketers to tailor advertisements to their interests. Moreover, when Americans are informed of three common ways that marketers gather data about people in order to tailor ads, even higher percentagesbetween 73% and 86%--say they would not want such advertising.These are two findings from the first nationally representative telephone (wireline and cell phone) survey to explore Americans' opinions about behavioral targeting by marketers, a controversial issue currently before government policymakers. Behavioral targeting involves two types of activities: following users' actions and then tailoring advertisements for the users based on those actions. While privacy advocates have lambasted behavioral targeting for tracking and labeling people in ways they do not know or understand, marketers have defended the practice by insisting it gives Americans what they want: advertisements and other forms ...