Articles in 2011

Sepsis is associated with a hyperinduction of proinflammatory cytokines. ATF3, a transcription factor, is induced in macrophages under conditions of endotoxic shock and downregulates expression of cytokines, including interleukin-6 (IL-6). Although ATF3 may thereby mitigate the severity of sepsis, Hoetzenecker et al. now show that endotoxin-induced ATF3 increases the susceptibility of mice to secondary pathogenic infections due to suppression of IL-6. Their findings suggest that temporal modulation of ATF3 may be important for the successful resolution of sepsis and the ensuing sepsis-associated immunosuppression.

Salmonella infection is a common complication in people with malaria. Here the authors show that induction of heme oxygenase-1, a mechanism of tolerance to malaria, impairs resistance to Salmonella infection by limiting production of bactericidal reactive oxygen species.

The authors identify a set of microRNAs regulated by EGFR and MET that are involved in the oncogenic signaling exerted by these receptors and also modulate the response of tumors to targeted EGFR inhibition. These results shed light on the known contribution of MET to therapy resistance and suggest that MET-regulated microRNAs can be key mediators of its effects and potential markers of clinical utility.

The authors find a reciprocal negative regulation loop between TCTP and P53. TCTP modulates P53 by competing with NUMB for MDM2 binding and increasing MDM2-mediated degradation of P53. This is reciprocated by p53's direct transcriptional repression of TCTP. Some human breast tumors have increased amounts of TCTP, which only in some cases correlateswith decreased P53 activity, and elevated TCTP is associated with poor prognosis and may influence P53-regulated stemness of tumor cells.

This report uncovers a role for the mRNA binding factor CPEB4 in cancer. CEPB4 is upregulated in human pancreatic adenocarcinomas and glioblastomas, where it supports tumor growth by providing translational activation of normally silent mRNAs, including tPA, an important contributor to malignancy. The findings illustrate that altered post-transcriptional regulation of gene expression may be an important contributing factor to cancer.

The cytokine PDGF has multiple effects on the vasculature and influences tumor growth and progression. Yuan Xue et al. uncover a new role for PDGF as a regulator of hematopoiesis and provide a unifying mechanism by which PDGF induction of the cytokine erythropoietin in stromal cells underlies PDGF's effects on both hematopoiesis and the tumor vasculature.

Steven Artandi and his colleagues have found that dedifferentiation and proliferation of kidney podocytes as a result of TERT or Wnt signaling leads to a collapsing glomerulopathy phenotype in mice, similar to that seen in HIV-associated nephropathy (HIVAN) in humans, and that inhibiting these pathways corrected disease progression. They also found that TERT expression and Wnt activity is elevated in a mouse model of HIVAN and in human HIVAN renal samples, suggesting possible targets to treat this disease.

Graft-versus-host disease (GVHD) can be a life-threatening complication of bone marrow transplantation (BMT). Understanding the mechanisms causing GVHD is important to developing treatments or preventive therapies. In this issue, Koyama et al. report the surprising finding that recipient nonhematopoietic antigen-presenting cells, rather than dendritic cells, are the crucial factor in inducing CD4⁺ T cell–dependent GVHD and death in mice.

Bone marrow-derived mesenchymal stem cells (BMMSCs) have so far failed to live up to their potential as a treatment for the repair of large bone defects. Songtao Shi and his colleagues now show that this may be due to their apoptosis mediated by resident T cells in the wound as a result of excess IFN-γ and TNF-α signaling. They show that reducing the levels of these cytokines, including through the local administration of aspirin, markedly increases the survival of implanted BMMSCs and improves bone wound healing in a mouse model.

Polly Matzinger and her colleagues have shown that in the absence of B cells, and in the presence of the microbiota, the intestinal epithelium launches its own immune defense mechanisms. However, this comes at the expense of metabolic programs involved in fat absorption by the gut. These results could explain the lipid malabsorption often seen in humans with common variable immunodeficiency or with HIV infection.

Glycoconjugate vaccines—such as those targeting some bacteria—couple a glycan to a protein to provide T cell help to B cells and induce polysaccharide-specific IgGs. T cell help has been thought to be conferred by recognition of the protein portion by T cells. Dennis Kasper and his colleagues now report that a glycan-peptide conjugate can induce T cells specific for the glycan moiety, which could help inform future glycoconjugate vaccine development.

This report identifies a new contribution of members of the miR-200 family to tumorigenesis. miR-200a and miR-141 specifically regulate p38α, contributing to the cellular modulation of oxidative stress responses. In this role, the miRs can accelerate ovarian tumorigenesis but also endow cancer cells with increased sensitivity to ROS-inducing chemotherapy. This two-part effect is reflected on the distinct association of the miRs with patient survival and may be informative for treatment decisions.

The enzyme argininosuccinate lyase (ASL) generates the amino acid arginine, the precursor to both urea and nitric oxide. However, arginine supplementation is not sufficient to correct all of the symptoms of individuals with a congenital deficiency of this enzyme. Ayelet Erez et al. explain this paradox by showing that ASL has a role in nitric oxide synthesis that is independent of its catalytic activity and provide evidence that therapy with agents boosting nitric oxide levels might be beneficial in ASL-deficient individuals.

It is well regarded that insulin receptor signaling in the liver is key to proper metabolic control. Reza Zarnegar and his colleagues now show that the hepatocyte growth factor receptor, Met, physically interacts with the insulin receptor signaling complex, potentiating the latter's signaling. They also show that Met signaling restores insulin responsiveness in a mouse model of insulin resistance, suggesting a potentially new therapeutic avenue to treat prediabetes.

The hormone aldosterone can damage the heart after myocardial infarction, such that drugs that inhibit its action are often prescribed. B. Julie He et al. now uncover a new pathway underlying the detrimental effects of aldosterone action: oxidation of the enzyme Ca²⁺/calmodulin-dependent protein kinase II leads to its activation and increased expression of the metalloprotease MMP9 in cardiac muscle cells, thereby promoting cardiac rupture.

Helga Ellingsgaard et al. show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy.

Fahumiya Samad and her colleagues have shown that the serine protease tissue factor, a key regulator of coagulation, has a role in obesity and metabolic disease. They find that tissue factor signaling in adipocytes promotes obesity, whereas its signaling in adipose tissue macrophages promotes local inflammation and insulin resistance.

The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis.

Séverine Coulon et al. identify a new mechanism regulating red blood cell production through transferrin receptor engagement. By binding this receptor on erythroblasts, the polymeric form of immunoglobin A1 (pIgA1) or iron-loaded transferrin acts in conjunction with erythropoietin to promote erythroblast maturation. Administration of either pIgA1 or iron-loaded transferrin accelerated recovery from anemia in mice, suggesting that these findings may have therapeutic implications.

Ron Evans and his colleagues have shown that excess thyroid hormone receptor signaling during embryonic development in mice impairs the differentiation of type I pneumocytes, a key lung cell type needed for proper gas exchange. They also show that treatment with antithyroid drugs during this stage of development rescues the defect in lung maturation, suggesting a possible therapy for some children born with respiratory distress syndrome.