Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor

Abstract

Objective. Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA).Methods. Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction.Results. HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA. Conclusion. The data indicate that TNF decreases

A carbohydrate fraction, AIP1 from Artemisia iwayomogi suppresses pulmonary eosinophilia and Th2-type cytokine production in an ovalbumin-induced allergic asthma. Down-regulation of TNF-α expression in the lung

“…However, TNF-α down-regulates the IFN-gamma-induced class II expression in differentiated cells such as human skin fibroblasts or activated macrophages. Such a reduced expression of class II molecules could decrease the capacity of antigenpresenting cells to stimulate Tcells [49]. Dendritic cells (DC), the most potent antigen-presenting cells, can be generated from bone marrow (BM) precursor cells in the presence of GM-CSF and IL-4.…”

Efficacy of Combination Therapy with rhTNFR:Fc and Methotrexate in the Patients with Disease-modifying Antirheumatic Drug -resistant Rheumatoid Arthritis

“…TNF antagonists may block this TNF-dependent suppression of HO-1 expression, resulting in an amelioration of inflammation [7].TNF decreases HLA-DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA-DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells [8]. As compared with oral methotrexate, subcutaneous etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis [5].…”

The immune system and postmenopausal osteoporosis

“…The increase in TNF produced by T cells during estrogen deficiency is explained by the increased expression of Class II TransActivator (CIITA), a transcriptional co-activator acting on MHCII promoter, with the final effect of up-regulation of expression of MHCII on macrophages (Cenci et al, 2003;Kim et al, 2010;Mueller et al, 2005), this subsequently expands the proliferation and lifespan of bone marrow T cells (Cenci et al, 2003;Gao et al, 2007). RANKL-expression on lymphocytes and marrow stromal cells is significantly elevated during estrogen deficiency in humans and correlates directly with increases in bone resorption markers and inversely with serum estrogen levels (Eghbali-Fatourechi et al, 2003).…”