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Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. [...]

doi:10.1172/JCI60006. Introduction TNF plays an important role in inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease (IBD), and psoriasis (1, 2). Biological drugs that inhibit TNF are effective, despite [...], Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1-/- mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1-/- mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1-/- mice showed no change in sensitivity to TNF, Jnk2-/- mice were significantly protected against TNF, identifying JNK2 as an essential player in inflamma-tion induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1-/- and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.

Introduction The tumor microenvironment generates a complex cytokine network that influences malignant cell proliferation, metastasis, angiogenesis, and the composition of the leukocyte infiltrate. This cytokine network also subverts adaptive immunity [...], Cytokines orchestrate the tumor-promoting interplay between malignant cells and the immune system. In many experimental and human cancers, the cytokine TNF-α is an important component of this interplay, but its effects are pleiotropic and therefore remain to be completely defined. Using a mouse model of ovarian cancer in which either TNF receptor 1 (TNFR1) signaling was manipulated in different leukocyte populations or TNF-α was neutralized by antibody treatment, we found that this inflammatory cytokine maintained TNFR1-dependent IL-17 production by [CD4.sup.+] cells and that this led to myeloid cell recruitment into the tumor microenvironment and enhanced tumor growth. Consistent with this, in patients with advanced cancer, treatment with the TNF-α-specific antibody infliximab substantially reduced plasma IL-17 levels. Furthermore, expression of IL-1R and IL-23R was downregulated in [CD4.sup.+][CD25.sup.-] cells isolated from ascites of ovarian cancer patients treated with infliximab. We have also shown that genes ascribed to the Th17 pathway map closely with the TNF-α signaling pathway in ovarian cancer biopsy samples, showing particularly high levels of expression of genes encoding IL-23, components of the NF-κB system, TGF-β1, and proteins involved in neutrophil activation. We conclude that chronic production of TNF-α in the tumor microenvironment increases myeloid cell recruitment in an IL-17-dependent manner that contributes to the tumor-promoting action of this proinflammatory cytokine.

Blood vessels have myriad functions, including contraction/relaxation, barrier function, thrombosis/hemostasis, and transport. Following injury, complex mechanisms of wound healing and resolution are triggered in order to return the vessel to [...], Arterial injury results in the formation of neointimal lesions. Lack of resolution of the pathologic neointima leads to stenosis, tissue ischemia, and organ dysfunction. In this issue of the JCI, Kovacic et al. show that, in response to arterial injury in mice, the cytokine TNF-α triggers a novel signaling pathway involving the combinatorial action of two transcription factors, STAT3 and NF-κB (p65 subunit), in VSMCs (see the related article beginning on page 303). Upon activation, these factors turn on transcription of a potent T cell chemokine, RANTES, which selectively recruits T cells into the vessel wall as part of the vascular wound-healing response.

People with cancer typically experience an overall decline in weight and muscle strength-a state referred to as cachexia. Cachexia is the major contributor to morbidity and premature mortality from cancer [...]