Commentary
Abstract
In this issue of the JCI, Bowers et al. show that the common polymorphism of the cardiac voltage-gated sodium channel, type Vα (SCN5A), designated S1103Y, found in African Americans is associated with an increased risk of sudden infant death syndrome (SIDS). Wild-type and mutant SCN5A channels both functioned typically under normal conditions in vitro, but exposure to acidic intracellular pH levels such as those found in respiratory acidosis — a known risk factor for SIDS — produced abnormal gain-of-function late reopenings of S1103Y channels, behavior that is often associated with cardiac arrhythmias. These pathologic late reopenings were suppressed by low levels of the channel-blocking drug mexiletine. These findings provide an excellent illustration of a causal relationship between the interaction of the environment and genetic background in SIDS and also raise interesting questions about the linkage of a genetic abnormality with a clinical phenotype.
Authors
Jonathan C. Makielski
Abstract
Mucous hypersecretion is a major cause of airway obstruction in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. EGFR ligands and IL-13 are known to stimulate mucous induction, but the detailed mechanisms of epithelial mucous regulation have not been well defined. In this issue of the JCI, Tyner et al. show, in a mouse model of chronic mucous hypersecretion, that ciliated epithelial cell apoptosis is inhibited by EGFR activation, allowing IL-13 to stimulate the differentiation of these cells into goblet cells, which secrete mucus. In defining this coordinated, 2-step process, we can consider the therapeutic effects of blocking mucous production. This begs the question, Is it possible to reduce airway obstruction in chronic lung disease by inhibiting EGFR activation and/or by inhibiting IL-13?
Authors
Lauren Cohn
Abstract
Previous studies suggest that insulin can inhibit hepatic glucose production (HGP) by both direct and indirect actions. The indirect effects include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid levels, reduction of the amount of gluconeogenic precursor supplied to the liver, and change in neural input to the liver. A study in this issue of the JCI demonstrates that, in overnight-fasted dogs, an acute, selective increase of portal insulin induces a rapid inhibition of HGP, and a 4-fold rise in head insulin level does not enhance the inhibition of HGP in response to portal insulin infusion. This study demonstrates that insulin’s direct effects on the liver dominate the control of HGP. These data balance previous studies in mice that suggested that indirect effects of insulin via the hypothalamus are the primary determinant of HGP.
Authors
Jean Girard
Abstract
Upper gastrointestinal dysfunction occurs frequently in diabetes and potentially contributes to both abdominal symptoms and impaired glycemic control; conversely, variations in blood glucose concentration reversibly affect gut motility in humans. In this issue of the JCI, Anitha et al. report apoptosis of rodent enteric neurons under hyperglycemic conditions, both in vitro and in vivo, associated with impaired PI3K activity and preventable by glial cell line–derived neurotrophic factor. These observations add to recent insights gained from animal models regarding the etiology of diabetic gastrointestinal dysfunction, but investigators must strive to translate animal data to human diabetes.
Authors
Christopher K. Rayner, Michael Horowitz
Abstract
Phagocytosis is a key process in protection of the host against pathogens and in provision of antigens for the immune response. Synergism between C3b and IgG and their receptors in promoting adherence to and then ingestion of an antigen has been recognized for decades. Only more recently, however, has cross-talk between another complement activation fragment, the anaphylatoxin C5a, and Fcγ receptors (FcγRs) been defined. In this issue of the JCI, C5a is shown to signal, via its receptor, the upregulation of activating (proinflammatory-type) FcγRs. Moreover, engagement of FcγRs by the IgG-bearing immune complex instructs the cell to synthesize more C5, from which C5a is derived. Thus, this work establishes a feedback loop whereby FcγR expression and function are enhanced, a very desirable event in concert with an infection but potentially deleterious in autoimmunity.
Authors
John P. Atkinson
Abstract
Obesity is associated with increased macrophage infiltration of adipose tissue, and these macrophages may be an important component of the chronic inflammatory response playing a crucial role in the development of insulin resistance. This prompts the question as to how macrophages infiltrate obese adipose tissue. In this issue of the JCI, Weisberg et al. show the importance of C-C motif chemokine receptor 2 (CCR2) in macrophage recruitment to adipose tissue and the development of obesity and its complications.
Authors
Jaap G. Neels, Jerrold M. Olefsky
Abstract
Some forms of hypertrophic cardiomyopathy (HCM) are caused by mutations in cardiac sarcomeric genes, but environmental factors are believed to influence the hypertrophic response. A highly variable but potentially significant environmental factor is diet. Since soy-rich diets have been speculated to confer protection against cardiovascular disease, Stauffer et al. have explored the influence of a soy diet on cardiac growth and function in a transgenic mouse model of HCM. They report that mice fed a soy diet exhibited significantly worse HCM than mice fed a soy-free (milk protein) diet. This study provides the first evidence of an environmental modifier — diet — on the hypertrophic phenotype and has implications for the way in which disease phenotypes are assessed in genetically altered murine models of disease.
Authors
Cathy J. Hatcher, Craig T. Basson
Abstract
In the last 5 years, global gene expression profiling has allowed for the subclassification of the heterogeneous disease of breast cancer into new subgroups with prognostic significance. However, for most subgroups, the nature of the contributions of individual genes to the clinical phenotypes remains largely unknown. In this issue of the JCI, Moyano and colleagues further examine the oncogenic potential of the small heat shock protein α-basic–crystallin, commonly expressed in tumors of the basal-like breast cancer subtype associated with poor prognosis, and show that it is an oncogenic protein in the breast.
Authors
Sofia K. Gruvberger Saal , Ramon Parsons
Abstract
The low molecular weight region of the serum peptidome contains protein fragments derived from 2 sources: (a) high-abundance endogenous circulating proteins and (b) cell and tissue proteins. While some researchers have dismissed the serum peptidome as biological trash, recent work using mass spectrometry–based (MS-based) profiling has indicated that the peptidome may reflect biological events and contain diagnostic biomarkers. In this issue of the JCI, Villanueva et al. report on MS-based peptide profiling of serum samples from patients with advanced prostate, bladder, or breast cancer as well as from healthy controls. Surprisingly, the peptides identified as cancer-type–specific markers proved to be products of enzymatic breakdown generated after patient blood collection. The impact of these results on cancer biomarker discovery efforts is significant because it is widely believed that proteolysis occurring ex vivo should be suppressed because it destroys endogenous biomarkers. Villanueva et al. now suggest that this suppression may in fact be preventing biomarker generation.
Authors
Lance A. Liotta, Emanuel F. Petricoin
Abstract
Gastric mucosa-associated lymphoid tissue (MALT) lymphomas can arise in a variety of extranodal sites. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations, all affecting the NF-κB pathway, have been implicated in the development and progression of MALT lymphoma. The most common is the translocation t(11;18)(q21;q21), which results in a fusion of the cIAP2 region on chromosome 11q21 with the MALT1 gene on chromosome 18q21 and is present in more than one-third of cases. The frequency of this translocation is site-related: common in the gastrointestinal tract and lung, rare in conjunctiva and orbit, and almost absent in salivary glands, thyroid, liver, and skin. In this issue of the JCI, Hu et al. add to our understanding of the molecular consequences of this translocation, showing that its fusion product, cIAP2-MALT1, may concomitantly contribute to lymphomagenesis both as a tumor suppressor gene and as an oncogene.
Authors
Francesco Bertoni, Emanuele Zucca
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