TNF receptor subtype signalling: Differences and cellular consequences

MacEwan, David J.

doi:10.1016/s0898-6568(01)00262-5

Cited by 557 publications

(440 citation statements)

References 375 publications

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“…TNF is synthesized as a monomeric type-2 transmembrane protein (tmTNF) that is inserted into the membrane as a homotrimer and cleaved by the matrix metalloprotease TNF-α converting enzyme (TACE; ADAM17) to a soluble circulating trimer (solTNF); both tmTNF and solTNF are biologically active [7,8]. The balance between tmTNF and solTNF signaling is influenced by cell type, activation status of the cell, the stimulus eliciting TNF production, TACE activity, and expression of endogenous TACE inhibitors leading to divergent TNF-mediated effects on cellular viability [9,10].…”

Section: Introductionmentioning

confidence: 99%

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

119

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Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lung. Given that there is significant literature supporting the pathobiologic role of TNF-α in asthma, mainly in severe refractory asthma, and COPD, TNF-α inhibitors (infliximab, golimumab and etanercept) are now regarded as potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-α inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-α inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-α, perhaps in a more carefully selected patient group. TNF-α treatment should therefore not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-α inhibitors.

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Section: Introductionmentioning

confidence: 99%

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

119

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“…The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types.…”

Section: Introductionmentioning

confidence: 99%

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

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TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

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“…The apoptotic signal induced by TNF-a is activated primarily through cell surface membrane-associated caspase-8. 8 The resistant HeLa cells did not display reduced Bid, a key protein bridging caspase-8 and caspase-9 signals (data not shown). Additionally, overexpression of DDB2 failed to modify cisplatin-induced apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 89%

“…Sequential activation of apoptotic signal from procaspase-8 to downstream execution caspases has been well studied. [6][7][8] However, the upstream signal of caspase-8 is less understood. p38MAPK is one of the stress kinases, transiently activated by a variety of stimuli, including UV and cytokines, through MEK-3 and MEK-6, 9,10 p38MAPK mediates TNF-a induced NF-kB activation and the induction of interleukin-6.…”

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confidence: 99%

Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance

Sun

Chao

2005

Intl Journal of Cancer

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Our previous study demonstrated that DDB2, a DNA repair protein, attenuates cell surface membrane-associated death signal induced by UV or FasAb; DDB2 is overexpressed in cisplatinselected cells. However, the molecular mechanism underlying the protective role of DDB2 along the apoptotic pathway remains unknown. Our study identified the cross-resistance of the cisplatinselected cells to tumor necrosis factor-a (TNF-a). Since knockdown of the DDB2 level rendered cells (HR18) sensitive to the treatment, the cell sensitivity to TNF-a appears inversely proportional to the cellular level of DDB2. Treatment of HeLa cells with TNF-a transiently induced activation of p38MAPK signal, but this induction was significantly reduced in the resistant cells. Overexpression of DDB2 attenuated the activation of p38 in cells. TNF-a-induced apoptotic signals, represented by caspase-8 and downstream substrate cleavage, were reduced in resistant cells compared to their sensitive counterparts. Inhibition of p38 signal by SB202190 clearly attenuated TNF-a-induced apoptotic signals. Moreover, overexpression of DDB2 in HR18 cells also attenuated TNF-a induced caspase activation. These results suggest that p38MAPK activation may be a key upstream signal of TNF-a-induced apoptosis and that attenuation of p38 signal by DDB2 overexpression may be responsible for acquired TNF-a resistance. ' 2005 Wiley-Liss, Inc.

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TNF receptor subtype signalling: Differences and cellular consequences

Cited by 557 publications

References 375 publications

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance

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TNF receptor subtype signalling: Differences and cellular consequences

Cited by 557 publications

References 375 publications

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance

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Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis