IL-23 induces the differentiation of naive CD4+ T cells into highly pathogenic helper T cells (Th17/ThIL-17) that produce IL-17, IL-17F, IL-6, and TNF-α, but not IFN-γ and IL-4. Two studies in this issue of the JCI demonstrate that blocking IL-23 or its downstream factors IL-17 and IL-6, but not the IL-12/IFN-γ pathways, can significantly suppress disease development in animal models of inflammatory bowel disease and MS (see the related articles beginning on pages 1310 and 1317). These studies suggest that the IL-23/IL-17 pathway may be a novel therapeutic target for the treatment of chronic inflammatory diseases.
Yoichiro Iwakura, Harumichi Ishigame
In blood vessels, endothelia are submitted to constant shear effects and are, under normal conditions, capable of responding to any variation in hemodynamic forces. Caveolae — 50- to 100-nm plasma membrane invaginations present at the surface of terminally differentiated cells and particularly enriched in ECs — are composed of a high sphingolipid and cholesterol content and the protein caveolin-1 (Cav-1). Previous studies have suggested that caveolae and endothelial Cav-1 may regulate the vascular response to altered shear stress. In this issue of the JCI, Yu et al. have examined the role of Cav-1/caveolae in the regulation of flow-induced alterations (i.e., mechanotransduction) in vessels from wild-type mice, Cav-1–deficient mice, and Cav-1–deficient mice re-expressing Cav-1 only in ECs. Their data suggest that caveolae/Cav-1 may act as sensors of altered shear stress and that they also organize the signaling response in stimulated ECs (see the related article beginning on page 1284).
Philippe G. Frank, Michael P. Lisanti
Most G protein–coupled receptors (GPCRs) probably exist as homodimers, but it is increasingly recognized that GPCRs may also dimerize with other types of GPCRs and that this physical interaction may affect the function of either receptor. A study in this issue of the JCI demonstrates how heterodimerization between prostaglandin E receptors and β2–adrenergic receptors (β2ARs) in airway smooth muscle cells results in uncoupling of β2ARs and a diminished bronchodilator response to β2AR agonists (see the related article beginning on page 1400). This illustrates what we believe to be a novel mechanism of receptor cross-talk and highlights the potential importance of GPCR heterodimerization in diseases such as asthma and how this could lead to the development of more specific therapies in the future.
Peter J. Barnes
Lectins like mannan-binding protein are part of the innate immune system. They circulate in association with serine proteases. Upon binding oligosaccharides, they activate the complement cascade analogous to the more familiar but evolutionarily more recent classical pathway, which is triggered by antibody binding to antigen. In this issue of the JCI, Selander et al. developed a sensitive and specific ELISA employing Salmonella-specific sugars to assess the activity of the lectin pathway of complement activation (see the related article beginning on page 1425). This more physiologic assay system allowed the investigators to rigorously define the requirements for lectin pathway activation. Furthermore, they uncovered an unsuspected means for this pathway to reach the desired critical step of activation of the opsonin C3. These types of functional assays will eventually replace the more laborious, less physiologic, and less informative approaches currently in use to monitor complement activation.
John P. Atkinson, Michael M. Frank
To avoid toxic overload of cholesterol in peripheral cells, the reverse cholesterol transport pathway directs excess cholesterol through HDL acceptors to the liver for elimination. In this issue of the JCI, a study by Matsuura et al. reveals new features of this pathway, including the importance of the ATP-binding cassette transporter G1 in macrophages and apoE in cholesteryl efflux from cells to cholesterol ester–rich (CE-rich) HDL2 acceptors (see the related article beginning on page 1435). One proposal for boosting reverse cholesterol transport has been to elevate plasma HDL levels by inhibiting CE transfer protein (CETP), which transfers CE from HDL to lower-density lipoproteins. However, there has been concern that large, CE-rich HDL2 generated by CETP inhibition might impair reverse cholesterol transport. ApoE uniquely facilitates reverse cholesterol transport by allowing CE-rich core expansion in HDL. In lower species, these large HDLs are not atherogenic. Thus, CETP might not be essential for reverse cholesterol transport in humans, raising hope of using a CETP inhibitor to elevate HDL levels.
Robert W. Mahley, Yadong Huang, Karl H. Weisgraber
Sepsis and sepsis syndrome are leading causes of mortality throughout the world. It is widely held that sepsis represents a dysregulated innate immune response to an offending pathogen. This immune response is often initiated via microbial products signaling through TLRs expressed on host immune cells. There is increasing evidence that this innate response can be dramatically influenced by the cellular redox state, and thus a better understanding of oxidative regulation of innate immunity could lead to new treatments for sepsis. In this issue of the JCI, Thimmulappa et al. show that nuclear factor-erythroid 2–related factor 2 (Nrf2), a member of the “cap’n’collar” family of basic region–leucine zipper transcription factors, which has previously been shown to be involved in the transcription of antioxidant gene expression in response to xenobiotic stress, is also a critical regulator of cellular oxidative stress in sepsis (see the related article beginning on page 984).
Jay K. Kolls
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent for the development of an aggressive hematologic neoplasia termed adult T cell leukemia/lymphoma (ATLL). Although the virus infects T cell subsets that display either CD4 or CD8 cell surface markers, the leukemic cell is exclusively of the CD4+ subtype. In the article by Sibon et al. in this issue of the JCI, the authors demonstrate that the molecular basis for clonal expansion differs between these 2 infected T cell populations (see the related article beginning on page 974). The molecular events associated with a preleukemic state, such as genomic instability, polynucleation, and cell cycle redistribution, were only observed in CD4+ T cells. This finding provides a molecular-based mechanism for the restriction of the leukemic phenotype to the CD4+ T cell subtype.
O. John Semmes
Enhanced signaling in myocytes by the G protein Gq has been implicated in cardiac hypertrophy and the transition to heart failure. α1-Adrenergic receptors (α1-ARs) are members of the 7-transmembrane-spanning domain (7-TM) receptor family and signal via interaction with Gq in the heart. The specific effects of a loss of α1-AR signaling in the heart are explored by O’Connell et al. in this issue of the JCI (see the related article beginning on page 1005). Paradoxically, gene ablation of the α1A and α1B subtypes in mice results in a maladaptive form of reactive cardiac hypertrophy from pressure overload, with a predisposition to heart failure. Thus signaling to the α1-AR (compared with signaling from other receptors such as angiotensin receptors, which also couple to Gq) appears to be specifically required for a normal hypertrophic response. This represents another example of how receptors that share common G proteins have diversified, developing unique signaling programs. These findings may have particular clinical relevance because of the widespread use of α1-AR antagonists in the treatment of hypertension and symptomatic prostate enlargement.
Stephen B. Liggett
Male and female external genitalia appear identical early in gestation. Testosterone exposure at 8–12 weeks’ gestation causes male differentiation. Female fetuses virilize if their adrenals secrete excessive levels of androgens, as occurs in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This can be ameliorated by administering dexamethasone to the mother. A study by Goto et al. in this issue of the JCI provides a rationale for this treatment by demonstrating that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate (see the related article beginning on page 953). Dexamethasone suppresses this axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not virilize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization.
Perrin C. White
RA is a quintessential autoimmune disease with a growing number of cells, mediators, and pathways implicated in this tissue-injurious inflammation. Now Kuhn and colleagues have provided convincing evidence that autoantibodies reacting with citrullinated proteins, known for their sensitivity and specificity as biomarkers in RA, enhance tissue damage in collagen-induced arthritis (see the related article beginning on page 961). This study adds yet another soldier to the growing army of autoaggressive mechanisms that underlie RA. With great success researchers have dismantled the pathogenic subunits of RA, adding gene to gene, molecule to molecule, and pathway to pathway in an ever more complex scheme of dysfunction. The complexity of the emerging disease model leaves us speechless. It seems that with this wealth of data available, we need to develop a new theory for this disease. We may want to seek guidance from our colleagues in physics and mathematics who have successfully integrated their knowledge of elementary particles and the complexity of their interacting forces by formulating the string theory.
Cornelia M. Weyand, Jörg J. Goronzy
No posts were found with this tag.