The turnover of Jun proteins, like that of other transcription factors, is regulated through ubiquitin-dependent proteolysis. Usually, such processes are regulated by extracellular stimuli through phosphorylation of the target protein, which allows recognition by F box-containing E3 ubiquitin ligases. In the case of c-Jun and JunB, we found that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. This pathway modulates cytokine production by effector T cells.

Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that

NF-κB activity in mammalian cells is regulated through the IκB kinase (IKK) complex, consisting of two catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ). Targeted deletion of Ikkβ results in early embryonic lethality, thus complicating the examination of IKKβ function in adult tissues. Here we describe the role of IKKβ in B lymphocytes made possible by generation of a mouse strain that expresses a conditional Ikkβ allele. We find that the loss of IKKβ results in a dramatic reduction in all peripheral B cell subsets due to associated defects in cell survival. IKKβ-deficient B cells are also impaired in mitogenic responses to LPS, anti-CD40, and anti-IgM, indicating a general defect in the ability to activate the canonical NF-κB signaling pathway. These findings are consistent with a failure to mount effective Ab responses to T cell-dependent and independent Ags. Thus, IKKβ provides a requisite role in B cell activation and maintenance and thus is a key determinant of humoral immunity.

No abstract

No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23-injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.

Bacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell IntroductionThe etiology of cutaneous T-cell lymphoma (CTCL), the most common type of T-cell lymphoma, remains poorly understood, but occupational exposures, infectious agents, and genetic mutations have been proposed as etiologic factors (see reviews [1][2][3][4][5] ). Mycosis fungoides (MF) and the leukemic variant Sezary syndrome (SS) are the 2 major clinical variants of CTCL. In the initial phase, which can last a number of years, MF presents as flat erythromatous skin patches, resembling chronic inflammation seen in chronic skin infections, psoriasis, and eczema. In the later stages, MF lesions gradually form plaques and overt tumors and eventually involve lymph nodes and internal organs. The early skin lesions in CTCL contain a heterogeneous cell population, including malignant cells that phenotypically resemble normal activated CD4 ϩ T lymphocytes and a mixture of nonmalignant tumor-infiltrating T cells, dendritic cells, macrophages, and other inflammatory cells. 1-5 SS, a leukemic and erythrodermic variant of CTCL, is characterized by the presence of circulating lymphocytes with atypical cerebriform nuclei (Sezary cells) in the skin, lymph nodes, and peripheral blood. 1 It is a more aggressive form of CTCL, with a mean survival of 3 years from the time of diagnosis.The role of chronic inflammation as a critical component in tumor progression has recently attracted much attention. It has become clear that the tumor microenvironment, which is largely made up of inflammatory cells, is a component of the malignant tumors (reviewed in de Visser et al 6 ). For instance, viral-antigenspecific, tumor-infiltrating CD4 ϩ T cells enhanced the neoplastic progression into invasive cancer in a model of squamous epithelial cell carcinogenesis induced by human papilloma virus oncogenes. 7 Furthermore, gene-expression profiling in follicular lymphomas indicated that the patient survival correlated with the molecular features of nonmalignant immune cells present in the tumor at diagnosis. 8 Several lines of evidence suggest that in CTCL there is a cross talk between malignant and nonmalignant T lymphocytes, keratinocytes, and dendritic cells. [9][10] During the course of the disease, a shift in the composition of infiltrating T cells appears to take place and the interactions between malignant and nonmalignant cells change. In the early stages of the disease, the infiltrate consists primarily of nonmalignant T-helper 1 (TH1) cells and cytotoxic CD8 ϩ T cells that appear to control the malignant cells via inhibitory cytokines such as interferon gamma and, possibly, direct cytotoxicity. [11][12][13] At the later stages of the disease, TH2 cells and cytokines seem to predominate. 11,12 Because malignant cells derived from MF tumors produce large amounts of IL-5, IL-6, and IL-13, it is likely ...

We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Psoriasis is a chronic inflammatory skin disease primarily driven by Th17 cells. IL-23 facilitates the differentiation and induces complete maturation of Th17 cells. Lesional psoriatic skin has increased levels of IL-23 and recent studies show that intradermal injections of IL-23 induce a psoriasis-like skin phenotype in mice. We have now characterized the IL-23-induced skin inflammation in mice at the molecular level and found a significant correlation with the gene expression profile from lesional psoriatic skin. As observed in psoriasis, the pathogenesis of the IL-23-induced skin inflammation in mice is driven by Th17 cells. We demonstrate a dramatic upregulation of IL-6 mRNA and protein after intradermal injections of IL-23 in mice. Using IL-6(-/-) mice we show that IL-6 is essential for development of the IL-23-elicited responses. Despite producing high levels of IL-22, IL-6(-/-) mice were unable to express the high-affinity IL-22 receptor chain and produced minimal IL-17A in response to intradermal injections of IL-23. In conclusion, we provide evidence for the critical role played by IL-6 in IL-23-induced skin inflammation and show that IL-6 is required for expression of IL-22R1A.