Objective. Numerous reports of the induction or worsening of psoriasis in patients treated with tumor necrosis factor (TNF) antagonists indicate that this is not a rare phenomenon. The etiology of this paradoxical clinical response remains unclear. The aim of this study was to describe similar cases, conduct a comprehensive analysis of the literature, explore possible immunologic mechanisms of action of this perplexing reaction, and recommend management options. Methods. A systematic literature review was performed using the PubMed and Medline databases (1996 to September 2007) searching the index terms "infliximab," "etanercept," "adalimumab," "tumor necrosis factor alpha inhibitor," and "TNF inhibitor," combined with the terms "psoriasis," "pustular," "skin," "rash," and "palmoplantar." All relevant articles in English were reviewed. Pertinent secondary references were also analyzed. Results. According to the literature, new-onset psoriasis may occur any time after initiation of TNF antagonist therapy, is often of an uncommon morphology, may respond to psoriasis treatments, and usually resolves with TNF discontinuation. The pathogenesis of this response appears to involve a disruption in cytokine balance following TNF inhibition, resulting in the up-regulation of plasmacytoid dendritic cells and the subsequent production of unopposed interferon-␣, following a triggering event in predisposed individuals. Conclusion. TNF antagonist-induced psoriasis is a newly recognized adverse effect of these medications that typically does not require therapy cessation. We recommend aggressive treatment of the skin disease and consideration of a change in the TNF antagonist if the lesions are unresponsive to conventional psoriasis treatment.

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.

Background & Aims Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other non-pathogens. Dendritic cells (DC) are thought to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DC in cancer. Therefore, we investigated whether high lipid content in liver DC affects induction of tolerance. Methods Mouse and human hepatic non-parenchymal cells were isolated by mechanical and enzymatic digestion. DC were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK)-cell, and NKT-cell co-culture assays, as well as in vivo. Results We observed 2 distinct populations of hepatic DC in mice and humans based on their lipid content and expression of markers associated with adipogensis and lipid metabolism. This lipid-based dichotomy in DC was unique to the liver and specific to DC, compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models—they activated T cells, NK cells, and NKT cells. Conversely, liver DC with low levels of lipid induced T-regulatory cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DC required their secretion of tumor necrosis factor-α and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity. Conclusions Human and mouse hepatic DC are comprised of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver.

Non-alcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DC) are antigen presenting cells with an emerging role in hepatic inflammation. We postulated that DC are important in the progression of NASH. We found that intrahepatic DC expand and mature in NASH liver and assume an activated immune-phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibro-inflammation. Our mechanistic studies support a regulatory role for DC in NASH by limiting sterile inflammation via their role in clearance of apoptotic cells and necrotic debris. We found that DC limit CD8+ T cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion Our findings support a role for DC in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH.