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1.  Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium 
The Journal of Clinical Investigation  2013;123(6):2590-2603.
TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a+/– or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.
doi:10.1172/JCI65624
PMCID: PMC3668821  PMID: 23676465
2.  Correction: Myeloid Takl Acts as a Negative Regulator of the LPS Response and Mediates Resistance to Endotoxemia 
PLoS ONE  2012;7(9):10.1371/annotation/74add513-eb1d-4fa1-ae2e-c3d2e7e735a0.
doi:10.1371/annotation/74add513-eb1d-4fa1-ae2e-c3d2e7e735a0
PMCID: PMC3463619
3.  Correction: Myeloid Takl Acts as a Negative Regulator of the LPS Response and Mediates Resistance to Endotoxemia 
PLoS ONE  2012;7(3):10.1371/annotation/ea1a4c80-8dfd-496a-a273-d74c1fd6e069.
doi:10.1371/annotation/ea1a4c80-8dfd-496a-a273-d74c1fd6e069
PMCID: PMC3319575
4.  Myeloid Takl Acts as a Negative Regulator of the LPS Response and Mediates Resistance to Endotoxemia 
PLoS ONE  2012;7(2):e31550.
TGFβ-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is considered a key intermediate in a multitude of innate immune signaling pathways. Yet, the specific role of TAK1 in the myeloid compartment during inflammatory challenges has not been revealed. To address this question, we generated myeloid-specific kinase-dead TAK1 mutant mice. TAK1 deficiency in macrophages results in impaired NF-κB and JNK activation upon stimulation with lipopolysaccharide (LPS). Moreover, TAK1-deficient macrophages and neutrophils show an enhanced inflammatory cytokine profile in response to LPS stimulation. Myeloid-specific TAK1 deficiency in mice leads to increased levels of circulating IL-1β, TNF and reduced IL-10 after LPS challenge and sensitizes them to LPS-induced endotoxemia. These results highlight an antiinflammatory role for myeloid TAK1, which is essential for balanced innate immune responses and host survival during endotoxemia.
doi:10.1371/journal.pone.0031550
PMCID: PMC3279403  PMID: 22348103

Results 1-5 (5)