Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.

Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf Δ AREmouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon γ and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38␣ and p38␤ MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38␤ (MAPK11) gene. p38␤ ؊/؊ mice were viable and exhibited no apparent health problems. The expression and activation of p38␣, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38␤ ؊/؊ mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38␤, suggesting that p38␣ is the predominant isoform involved in these processes. The p38␤ ؊/؊ mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38␤ ؊/؊ mice. As p38 is activated by tumor necrosis factor, the p38␤ ؊/؊ mice were crossed onto a TNF⌬ARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38␤. Together these results suggest that p38␣, and not p38␤, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38␤ during the development of p38 inhibitors.

Synovial fibroblasts from patients and mice with arthritis express autotaxin, and ablation of autotaxin in fibroblasts ameliorates disease.

Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.