Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2؊/؊ and wild-type mice (n ‫؍‬ 11-14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12-16 and 25-29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2؊/؊ mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2 ؊/؊ mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2؊/؊ mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2 ؊/؊ mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2 ؊/؊ mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.

Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small-molecule antagonists of the receptor of MCP-1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP-1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP-1/CCL2(-/-) and CCR2(-/-) mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP-1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP-1/CCL2/CCR2 axis in disease.

Interleukin-5 (IL-5) transgenic mice are highly resistant to primary infections with the intestinal nematode Nippostrongylus brasiliensis; few parasites are found in the intestines of infected animals, and egg production is minimal. While adult worms may be damaged in the intestine, larval migration, development, and viability may also be impaired in other tissues. This study addresses the migration of N. brasiliensis larvae through the skin and lungs and associated cellular responses in primary infections of IL-5 transgenic mice. Although some larvae may have been trapped and killed in the lungs of IL-5 transgenic mice, most apparently failed to reach this site. Two or more hours after infection of IL-5 transgenic mice, eosinophils were a major component of the cellular infiltrate at the subcutaneous site of injection, and localized eosinophil degranulation was extensive. Seventy-five to ninety-five percent of the larvae injected into subcutaneous air pouches in IL-5 transgenic mice were retained there for at least 24 h. In contrast, in nontransgenic mice, less than 20% of larvae could be recovered from the skin 2 or more h postinjection, and eosinophil activity was modest at all times. The data strongly suggest that eosinophils can restrict the movement of N. brasiliensis larvae in the first few hours of a primary infection and that this has profound effects on later stages of parasite development. Preexisting eosinophilia, due either to allergy or to infection with tissue-invasive helminth species, may therefore confer some degree of immediate and nonspecific resistance in primary infections with parasitic worms.

Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a mediator of inflammation that has been implicated in the pathogenesis of a wide variety of human diseases. CCR2, a heterotrimeric G-coupled receptor, is the only known receptor that functions at physiologic concentrations of MCP-1. Despite the importance of CCR2 in mediating MCP-1 responses, several recent studies have suggested that there may be another functional MCP-1 receptor. Using arterial smooth muscle cells (SMC) from CCR2(-/-) mice, we demonstrate that MCP-1 induces tissue-factor activity at physiologic concentrations. The induction of tissue factor by MCP-1 is blocked by pertussis toxin and 1,2-bis(O-aminophenyl-ethane-ethan)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, suggesting that signal transduction through the alternative receptor is G(alphai)-coupled and dependent on mobilization of intracellular Ca(2+). MCP-1 induces a time- and concentration-dependent phosphorylation of the mitogen-activated protein kinases p42/44. The induction of tissue factor activity by MCP-1 is blocked by PD98059, an inhibitor of p42/44 activation, but not by SB203580, a selective p38 inhibitor. These data establish that SMC possess an alternative MCP-1 receptor that signals at concentrations of MCP-1 that are similar to those that activate CCR2. This alternative receptor may be important in mediating some of the effects of MCP-1 in atherosclerotic arteries and in other inflammatory processes.

Infection of cervical keratinocytes by high-risk HPV is in-HPVs are etiologically involved in carcinoma of the uterine cervix. Among the nearly 90 HPV serotypes isolated to date, a subset of high-risk viruses has been found in over 90% of human cervical cancers. 1 These include HPV16 (detected in 50% of tumors), HPV18, HPV31 and HPV33. The products of the viral oncogenes E6 and E7 from high-risk viruses have been implicated in carcinogenesis because their expression is sufficient for the immortalization of primary human keratinocytes in vitro. 2-4 E6 targets p53 for ubiquitin-mediated degradation, while E7 binds and inactivates the product of the tumor-suppressor gene Rb. 5,6 Despite this efficient program for inactivating tumor-suppressor proteins, development of cervical carcinoma is a multistep process for which E6 and E7 are necessary but not sufficient. Other genetic changes are required, which may be a consequence, in part, of the chromosomal instability produced by expression of these oncogenes. 7 In addition, however, the host can mount an immune response against HPV, which keeps the infection in a clinically latent state, and this latency must be overcome for cervical cancer to appear. 1,8 -10 Very little is known about the regulation of the immune response directed against HPV-infected epithelial cells. Although epithelial cells can present antigen and release proinflammatory cytokines when activated, [11][12][13][14] there is little or no inflammation at the site of primary HPV infection, 8 and the few inflammatory cells that are present appear not to be activated. 15 In addition, as epithelial dysplasia worsens during progression toward cervical carcinoma, the cervical mucosa is gradually depleted of macrophages, T cells and Langerhans cells. 16 These observations suggest that HPV is capable of suppressing the host's immune and inflammatory responses to viral infection and transformation.One of the earliest cellular responses to injury or infection is the release of chemokines, which are low m.w. chemoattractant proteins that elicit local infiltration of inflammatory and immune cells. 17 The chemokine MCP-1 is particularly relevant in the setting of viral infection because of its ability to attract monocytes, memory T cells and NK cells in vivo. 18 However, even though MCP-1 expression is induced after infection by a variety of RNA and DNA viruses, MCP-1 expression is suppressed after epithelial cell infection by HPV in vitro. 19 This parallels the situation in vivo, where advancing cervical intraepithelial neoplasia is associated with loss of MCP-1 expression. 20 The mechanisms responsible for HPV-mediated suppression of MCP-1 expression are unclear. The present study was undertaken to examine the effects of HPV E6 and E7 on chemokine expression by primary epithelial cells of the reproductive tract. Surprisingly, we found that viral oncogenes selectively render MCP-1 unresponsive to induction by proinflammatory cytokines and that this refractoriness is also seen in most cervical carcinoma cell li...

In this study, interleukin-5 (IL-5) transgenic mice with lifelong eosinophilia were assessed for resistance to primary infections with two tissue-invading nematodes, Nippostrongylus brasiliensisand Toxocara canis. Relative to nontransgenic littermates, three lines of IL-5 transgenic mice with varying degrees of eosinophilia all displayed enhanced resistance to N. brasiliensis. Although the timing of final worm expulsion was similar in transgenic and nontransgenic hosts, intestinal worms in transgenic mice were fewer in number throughout infection, failed to increase in size over the course of the infection, and were much less fecund. In contrast, T. canis larvae were recovered in similar numbers from tissues of transgenic mice with “low” or “high” eosinophilia and from nontransgenic mice. These results and other data suggest that eosinophils can contribute to host resistance to some parasite species. Parasite transit time through the host may correlate with relative sensitivity to eosinophils.

Eosinophils have long been thought to be effectors of immunity to helminths but have also been implicated in the pathogenesis of asthma. Patterns of cytokine production in the host

Prazosin appeared highly beneficial for combat-related nightmares characteristic of post-traumatic stress disorder among troops recently returned from Operation Iraqi Freedom. These findings provide a rationale for a placebo-controlled trial to establish efficacy in this population.