http://www.jci.org/just-published en-us 2012 The American Society for Clinical Investigation http://www.jci.org/icons/banner/rss_title.gif http://content.jci.org http://www.jci.org/articles/view/46039 Ccnd1 mRNA. Mechanistically, we discovered that increased miR-21 expression facilitated cyclin D1 translation in the early phase of liver regeneration by relieving Akt1/mTOR complex 1 signaling (and thus eIF-4F–mediated translation initiation) from suppression by Rhob. Our findings reveal that miR-21 enables rapid hepatocyte proliferation during liver regeneration by accelerating cyclin D1 translation. ]]> info:doi/10.1172/JCI46039 American Society for Clinical Investigation http://www.jci.org/articles/view/46465 info:doi/10.1172/JCI46465 American Society for Clinical Investigation http://www.jci.org/articles/view/58431 cis-element upstream of the leptin (LEP) gene in human fat cells. Quantitative proteomics with affinity enrichment of protein-DNA complexes identified the transcription factor FOS-like antigen 2 (FOSL2) as binding specifically to the identified region, a result that was confirmed by ChIP. Knockdown of FOSL2 in human adipocytes decreased LEP expression, and overexpression of Fosl2 increased Lep expression in mouse adipocytes. Moreover, the elevated LEP expression observed in obesity correlated well with increased FOSL2 levels in mice and humans, and adipocyte-specific genetic deletion of Fosl2 in mice reduced Lep expression. Taken together, these data identify FOSL2 as a critical regulator of leptin expression in adipocytes. ]]> info:doi/10.1172/JCI58431 American Society for Clinical Investigation http://www.jci.org/articles/view/59097 Gnas^ΔCD4). Gnas^ΔCD4 CD4⁺ T cells had reduced cAMP accumulation and Ca²⁺ influx. In vitro and in vivo, Gnas^ΔCD4 CD4⁺ T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas^ΔCD4 CD4⁺ T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas^ΔCD4 CD4⁺ T cells, reinstated the PKA-dependent influx of Ca²⁺, and enhanced the ability of these cells to induce colitis. Our findings thus define an important role for cAMP in the differentiation of Th subsets and their subsequent inflammatory responses, and provide evidence that altering cAMP levels in CD4⁺ T cells could provide an immunomodulatory approach targeting specific Th subsets. ]]> info:doi/10.1172/JCI59097 American Society for Clinical Investigation http://www.jci.org/articles/view/59816 LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Leprlox^TB allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR. ]]> info:doi/10.1172/JCI59816 American Society for Clinical Investigation http://www.jci.org/articles/view/60329 info:doi/10.1172/JCI60329 American Society for Clinical Investigation http://www.jci.org/articles/view/60588 Cxcr2^–/– mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. The mechanisms underlying these phenotypes, however, are unclear. We report here that Cxcr2 on murine neutrophils inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis. Furthermore, enterocyte-derived Cxcl5 in the gut regulates IL-17/G-CSF levels and contributes to Cxcr2-dependent neutrophil homeostasis. Conversely, G-CSF was required for Cxcl5-dependent regulation of neutrophil homeostasis, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5^–/– and Cxcr2^–/– mice. Cxcr2^–/– mice constitutively expressed IL-17A and showed increased numbers of IL-17A–producing cells in the lung, terminal ileum, and spleen. Most IL-17–producing splenocytes were responsive to IL-1β plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment in Cxcr2^–/– mice markedly decreased IL-17A and G-CSF expression, neutrophilia, and marrow myeloid hyperplasia. These data suggest a critical role for Cxcr2, Cxcl5, and commensal bacteria in regulation of the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites and have implications for the development of treatments for pathologies resulting from either excessive or ineffective neutrophil responses. ]]> info:doi/10.1172/JCI60588 American Society for Clinical Investigation http://www.jci.org/articles/view/61226 + breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors. ]]> info:doi/10.1172/JCI61226 American Society for Clinical Investigation http://www.jci.org/articles/view/61498 TGFBR1) or TGF-β receptor type II (TGFBR2), such as those with Loeys-Dietz syndrome, have craniofacial defects and signs of elevated TGF-β signaling. Similarly, mutations in TGF-β receptor gene family members cause craniofacial deformities, such as cleft palate, in mice. However, it is unknown whether TGF-β ligands are able to elicit signals in Tgfbr2 mutant mice. Here, we show that loss of Tgfbr2 in mouse cranial neural crest cells results in elevated expression of TGF-β2 and TGF-β receptor type III (TβRIII); activation of a TβRI/TβRIII-mediated, SMAD-independent, TRAF6/TAK1/p38 signaling pathway; and defective cell proliferation in the palatal mesenchyme. Strikingly, Tgfb2, Tgfbr1 (also known as Alk5), or Tak1 haploinsufficiency disrupted TβRI/TβRIII-mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice, indicating that activation of this noncanonical TGF-β signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice. Thus, modulation of TGF-β signaling may be beneficial for the prevention of congenital craniofacial birth defects. ]]> info:doi/10.1172/JCI61498 American Society for Clinical Investigation