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TNF Produced by Distinct Types of Leukocytes: The Good and the Badumor necrosis factor-α (TNF-α) is a pleiotropic immunoregulatory cytokine initially brought to prominence because of its antitumor effects. It was later demonstrated that TNF is a critical mediator of host defense to bacterial infections, in particular, because of its role in granuloma formation. The “dark side” of TNF is best illustrated by its involvement in sepsis and in several autoimmune diseases with an inflammatory component. TNF is also involved in skin carcinogenesis and could be a critical player in other inflammation-induced cancers. Systemic TNF blockade represents a highly efficient therapy for patients with rheumatoid arthritis and Crohn’s disease, and trials are under way to evaluate the efficacy of TNF blockers in psoriasis and in cancer. Mice with complete or partial TNF ablation may serve as useful models to evaluate the consequences of TNF blockade. In particular, studies in mice have suggested the possibility of deleterious side effects to anti-TNF therapy, which has held true for a fraction of patients who have indeed developed various bacterial infections, including tuberculosis. We used Cre-loxP technology to generate a panel of novel mice with conditional TNF ablation in distinct types of immune cells. One possibility we wanted to evaluate was whether beneficial TNF could predominantly be coming from one cell type and harmful TNF from another. In collaboration with Lino Tessarollo, PhD (Mouse Cancer Genetics Program, NCI, Frederick) and our sister lab at the Engelhardt Institute of Molecular Biology in Moscow, we generated mice with highly efficient and specific TNF ablation in cells of the innate immune system, such as macrophages and neutrophils (M-TNF mice), as well as in both major types of lymphocytes (T-TNF and B-TNF mice). All these mice have shown distinct phenotypes, indicating important and non-redundant functions in vivo for TNF produced by macrophages, T cells, and B cells (Figure 1). Figure 1. Tumor necrosis factor (TNF)“floxed” mice were generated by homologous recombination in embryonic stem (ES) cells with subsequent removal of neo-cassette. Three different cell typespecific deleter mice were used to generate the experimental panel in the study. Beneficial (green) and detrimental (red) in vivo effects of TNF produced by various types of leukocytes are listed. LPS, lipopolysaccharide; SEB, staphylococcal enterotoxin B; MLys, macrophage lysozyme; loxP, target sequences for the site-specific Cre-recombinase. Mice with TNF ablation in macrophages and neutrophils produced almost no detectable systemic TNF in response to lipopolysaccharide (LPS) and were protected from LPSD-galactosamine (Dgal) liver toxicity. Under these challenges, both B-TNF and T-TNF mice had the wild-type phenotype. However, in models of toxicity in which T cells were activated by staphylococcal enterotoxin B (SEB) or concanavalin A (ConA), T-TNF mice showed protection from TNF-mediated toxicities. Thus, different toxic agents induce either macrophage/neutrophil or T cellderived TNF. Macrophage/neutrophil-derived TNF also turned out to be critical in resistance to the intracellular pathogen Listeria monocytogenes. Surprisingly, however, mice with TNF ablation only in T cells also showed defects in host defense against high doses of L. monocytogenes. Importantly, macrophages and neutrophils in T-TNF mice retained full ability to produce high levels of systemic TNF, as indicated by challenge experiments with LPS and other bacterial products. Why couldn’t this abundant TNF compensate for the lack of TNF produced by T cells? What is the intrinsic non-redundant role of T cellderived TNF? These questions remain to be answered. We hypothesize that T cells produce TNF in such a way that it either remains membrane bound or is released within the space of cell-to-cell contacts. A possible alternative is that in different in vivo situations, macrophages are desensitized and TNF may be produced only by T cells. Although B-TNF mice had a wild-type phenotype in these challenge models, TNF produced by B cells is critically involved in providing maintenance signals for the organized lymphoid tissues, such as in the spleen (Endres R et al. J Exp Med 189: 15968, 1999) or Peyer’s patches (Tumanov AV et al. J Immunol 173: 8691, 2004). Thus, TNF produced by each type of immune cell analyzed in our study may be both good and bad, depending on the pathophysiological model. It is conceivable that the thresholds for protective and deleterious TNF functions may differ, and this could be exploited in future protocols of therapeutic TNF ablation.
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