IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism

Rendon-Mitchell, B.; Ochani, Mahendar; Li, Jianhua; Han, Jaehee; Wang, Hong; Yang, Huan; Susarla, Srinivas M.; Czura, Christopher J.; Mitchell, Robert A.; Chen, Guoqian; Sama, Andrew E.; Tracey, Kevin J.; Wang, Haichao

doi:10.4049/jimmunol.170.7.3890

Cited by 291 publications

(309 citation statements)

References 69 publications

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“…TNF- exerts its effects through activation of TNFR1/2, which leads to a rapid activation of the JAK/STAT pathway. Some studies show macrophages produce TNF-, depending on IFN-γ, which activates macrophages, and which has been believed to use the JAK-STAT pathway (31). In the present study, the concentration of TNF- in BALF in rat pulmonary fibrosis treated by STAT1 ASON was decreased, and less expression of TNF- at an early stage would cause less acute inflammation and prevent chronic inflammation.…”

Section: Figure 4 Rt-pcr Results Of Type I Collagen (A and C) And supporting

confidence: 50%

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

et al. 2009

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Section: Figure 4 Rt-pcr Results Of Type I Collagen (A and C) And supporting

confidence: 50%

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

et al. 2009

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“…2A, lower row). In activated monocytes this phenomenon has been shown to precede secretion of HMGB1 in the extracellular environment [35,52]. We then checked if HMGB1 is (Fig.…”

Section: Resultsmentioning

confidence: 99%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the bestcharacterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. IntroductionDendritic cells (DC) are potent antigen-presenting cells bridging the innate and adaptive immune responses. To date, two subsets of DC have been identified in humans: myeloid DC and plasmacytoid DC (PDC), the latter also referred to as type I interferon (IFN-a)-producing cells [1][2][3][4][5][6]. PDC recognize viral or bacterial DNA patterns, consisting of unmethylated CpG motifs in the context of species-dependent surrounding sequences (CpG) [7]. As a consequence they produce, within a few hours, large amounts of . Based on their ability to induce IFN-a secretion by PDC, two types of CpG have been described: CpG 2216 (CpG-A), which induces high amounts of IFN-a, and CpG 2006 (CpG-B), which promotes survival, maturation and migration of PDC to the lymph nodes, but induces lower amounts of . PDC sustain the priming of naive T cells and their differentiation into Th1/Th2 effectors [15][16][17] or into regulatory T cells [16,[18][19][20][21][22].Recent studies shed light on the events involved in the recognition of microbial DNA by human PDC, the only subset of human DC that expresses the Toll-like receptor 9 (TLR9) [12]. Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24]. TLR9 activation leads to recruitment of the MyD88 adaptor protein and phosphorylation of the IL-1R-associated kinase (IRAK). Phosphorylated IRAK associates with the adaptor molecule TNF-associated factor 6 (TRAF6) [25]. Two separate signaling pathways, JNK and NF-jB, are then activated, promoting PDC maturation and survival. IFN-a induction, an event exclusively occurring in PDC, depends on the formation of a complex consisting of MyD88, TRAF6 and the IRF7 transcription factor, as well as on TRAF6-dependent ubiquitination [26].The events that determine the outcome of the interaction of PDC with T cells, and in particular the induction of effector or regulatory immune responses, are poorly characterized. Environmental signals that Here we report that HMGB1 is exported from the nucleus of PDC upon selective engagement of TLR9 an...

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“…Studies of murine erythroleukemia (MEL) cells have shown that extracellular export of HMGB1 is not dependent on the ER and the Golgi complex, but promoted by an increase of intracellular Ca 2ϩ and possibly by the activation of a Ca-dependent protein kinase C isoform (39). There is a limited amount of information on cytoplasmic HMGB1, which is packaged into a specific population of secretory lysosomes present in hematopoietic cells (40), before being released extracellularly (9,41). It is still unclear how HMGB1 is loaded into secretory lysosomes and whether HMGB1 plays a role in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Post-translational Methylation of High Mobility Group Box 1 (HMGB1) Causes Its Cytoplasmic Localization in Neutrophils

Ito

Fukazawa

Yoshida

2007

Journal of Biological Chemistry

193

178

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High mobility group box 1 (HMGB1) protein plays multiple roles in transcription, replication, and cellular differentiation. HMGB1 is also secreted by activated monocytes and macrophages and passively released by necrotic or damaged cells, stimulating inflammation. HMGB1 is a novel antigen of antineutrophil cytoplasmic antibodies (ANCA) observed in the sera of patients with ulcerative colitis and autoimmune hepatitis, suggesting that HMGB1 is secreted from neutrophils to the extracellular milieu. However, the actual distribution of HMGB1 in the cytoplasm of neutrophils and the mechanisms responsible for it are obscure. Here we show that HMGB1 in neutrophils is post-translationally mono-methylated at Lys 42 . The methylation alters the conformation of HMGB1 and weakens its DNA binding activity, causing it to become largely distributed in the cytoplasm by passive diffusion out of the nucleus. Thus, post-translational methylation of HMGB1 causes its cytoplasmic localization in neutrophils. This novel pathway explains the distribution of nuclear HMGB1 to the cytoplasm and is important for understanding how neutrophils release HMGB1 to the extracellular milieu. High mobility group box 1 (HMGB1)2 protein is one of the most abundant nonhistone chromosomal proteins in eukaryotic organisms. The primary sequences of HMGB1 in various higher organisms, from birds to mammals, show more than 90% homology with each other (1). The protein has multiple roles in transcription, replication, and cellular differentiation (2, 3). HMGB1 interacts with several transcription factors, thereby allowing them to perform their cellular roles. The phenotype of Hmgb1 knock-out mice confirmed the functional importance of HMGB1 as a regulator of transcription: they die shortly after birth and show a defect in the transcriptional control exerted by the glucocorticoid receptor (4). The subcellular distribution of the protein is tissue-specific: HMGB1 is located in both the nuclei and the cytoplasm of different tissues, such as lymphoid tissue, testis, neurons, and hepatocytes (5). Wang et al. (6) identified HMGB1 as a late mediator of endotoxin lethality in mice and showed that monocytes and macrophages stimulated by lipopolysaccharide (LPS), tumor necrosis factor (TNF) or interleukin-1 (IL-1) secrete HMGB1 in a delayed response. Patients with sepsis show an increased serum level of HMGB1, which is correlated with the severity of infection (7). Moreover, HMGB1 in monocytes and macrophages is extensively acetylated upon activation by LPS, causing localization of the protein to the cytosol (8). Cytosolic HMGB1 is then concentrated into secretory lysosomes and secreted when the cells receive an appropriate second signal (9). The recent discovery of extracellular HMGB1 as a proinflammatory mediator has been supported by a number of studies. In addition, HMGB1 is passively released from the nucleus to the extracellular milieu by cells that die as a result of necrosis or damage (10).Our previous studies showed that HMGB1 and HMGB2 are novel antigens of a...

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IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism

Cited by 291 publications

References 69 publications

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Post-translational Methylation of High Mobility Group Box 1 (HMGB1) Causes Its Cytoplasmic Localization in Neutrophils

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