We sought to compare subunits and protease activities of proteasomes isolated from resident versus TG-elicited peritoneal macrophages from several different inbred strains of mice (there was a 5–10 fold increase in the number of macrophages collected after TG-elicitation, as compared with resident macrophages), to determine whether this heterogeneity of cell type with respect to proteasome structure could contribute to heterogeneity of results described in the literature (Fig. 2). We compared resident versus TG-elicited macrophages from BALB/c (BC), C57BL/6 (B6) mice (wild-type), C3H/HeN (wild-type), and C3H/HeJ mice (24). As demonstrated by Western analysis, most of the macrophages obtained from various mouse strains showed heterogeneity with respect to proteasome subunits. BC resident macrophages expressed predominantly X, Y, and LMP2 subunits, with undetectable levels of LMP7, and barely detectable LMP10. Subunit Z was not present in significant amounts. After TG-elicitation, levels of X and Y subunits decreased (BC-TG), and LMP2 and LMP10 appeared to increase, but there was no detectable increase in expression of LMP7, as shown in Fig. 2, Table 1. B6 resident macrophages lacked X and Z subunits as compared with RAW 264.7 macrophages, and expressed predominantly Y, LMP2, and LMP10; LMP7 was barely detectable. TG-elicited B6 macrophages differed from resident B6 macrophages by expressing LMP7 much more prominently. Interestingly, resident macrophages from C3H/HeJ mice (LPS non-responders) showed lower levels of LMP7 and LMP10 than C3H/HeN (wild-type) mice. Moreover, upon TG treatment of C3H/HeJ mice, X and Y subunit expression was down-regulated and there were slight elevations of LMP7 and LMP10 expression. TG-elicited C3H/HeN macrophages induced slight reductions and increases in expression of Y and LMP7, respectively. There is a dramatic shift for macrophages obtained from B6 mice, C3H/HeJ and C3H/HeN mice, and a minor shift toward increased LMP7 expression for BC macrophage that corresponds to a change in specificity of the proteasome's protease activities from postacidic to chymotrypsin-like and trypsin-like activities (data not presented). These mouse macrophages are very active in inducing LPS-induced TNF-α and NO. However, at times, when TG treatment causes an increase in X, Y, and Z subunits, a decrease in TNF-α and NO induction as compared with resident cells was observed (data not presented). This suggests that some mouse peritoneal macrophages that contain at least five to six proteasome subunits including LMP7 are very active in inducing NO and cytokines in response to LPS. Cells are clearly heterogeneous with respect to proteasome subunits and cells were selected based on differential proteasome structures.
Proteasome's proteases are upregulated during inflammation and downregulated during tolerance in RAW 264.7, THP-1, and CD14+ monocytes. Reprogramming of tolerant cells leads to down-regulation of proteasome subunits
Our goal was to test the hypothesis that initial interaction of LPS with host macrophages reprograms proteasome's subunit structure and enzymatic activities, leading to LPS-induced pro-inflammatory responses, followed by tolerance. Human blood CD14+ monocytes, RAW 264.7 cells, and PMA-differentiated THP-1 cells were placed in various experimental groups designated as follows: MM, ML, LM, and LL, as described under the Methods section.
As shown in Figure 3A and B, the MM group served as a control, and ML (first LPS treatment, mimicking an initial inflammatory response) showed 81.3 and 44.8-fold upregulation in levels of TNFα protein and 31.3 and 27.8-fold increased mRNA (δCT values) after 4 h, in THP-1 and RAW 264.7 cells, respectively, as expected. However, when cells were pretreated with LPS for 24 h, washed, and then treated with medium (LM) or LPS a second time (LL, representing LPS induced tolerance), TNFα protein expression, and mRNA levels were reduced to only 0.77 fold (RAW 264.7) and 0.69 fold (THP-1), compared with ML group. Thus, initial LPS treatment induced a state of tolerance, demonstrated by reduced levels of expression of TNFα protein and mRNA on re-exposure to LPS, in both cell lines. Next, we examined whether tolerant state in LM cells could be reversed by treatment with IFN-γ. In order to test this, tolerant cells (LM) were pretreated with IFN-γ for 4 h followed by exposure to medium (LM+IFN-γ) or LPS (LM+IFN-γ+LPS) for another 4 h. Our data demonstrated that IFN-γ+LPS treatment completely reversed the state of tolerance; and there was a concomitant 2.85 fold (RAW 264.7) and 17.8 fold (THP1) upregulation of TNF-α protein; and 7.23 fold (RAW 264.7) and 4.81 fold (THP1) increase in gene expression, respectively. (Fig. 3, A and B), In contrast, there was no effect on NO production in tolerant RAW 264.7 cells (Fig. 3C). Besides, THP-1 cells and human monocytes (data not presented) did not produce NO in response to LPS, under any of the conditions tested (Fig. 3C).
In order to determine whether the results of experiments described above, for LPS tolerance, were associated with changes in various protease subunits, we performed identical experiments with respect to LPS or media exposure, and IFN-γ rescue, but measured expression of proteasome subunits (Fig. 4, A–D). In RAW 264.7 cells treated with media initially (i.e., no induction of LPS tolerance), followed by 4 or 24 h of exposure to LPS (ML), there was a substantial increase in production of mRNA for all proteasome subunits; most robust changes were observed for X, Y, Z and LMP subunits after 4 h of LPS exposure (Fig. 4, A and B), but less upregulation at 24 h (Fig. 4, C and D). There was a significant downregulation in expression of all subunits during LM and LL treatments. Treatment of tolerized cells with IFN-γ alone did not rescue, but IFN-γ and LPS, significantly upregulated expression of all LMP and X subunits (Fig. 4, A–D).
In contrast to RAW 264.7 cells, PMA-treated THP1 cells showed no significant effect on X, Y, and Z subunit expression in any of treatments (data not shown), but there was significant upregulation of all three LMP subunits at 4 h after LPS exposure (P <0.05) (Fig. 4E). Moreover, first LPS treatment resulted in significantly lower levels of mRNA for LMP7 and LMP2 in tolerized (LM), compared with non-tolerized cells (ML) (Fig. 4E), and after 24 h LPS treatment, all three LMP subunits were downregulated in tolerized THP1 cells (LM and LL; P <0.05) (Fig. 4F). Interestingly, IFN-γ treatment alone or IFN-γ and LPS was able to upregulate two or three LMP subunits in THP1 cells that were re-exposed to LPS for 4 and/or 24 h (Fig. 4, E and F).
In order to determine whether the results of experiments described above, for LPS tolerance, were associated with changes in various protease activities of the proteasome, we performed identical experiments to those described above with respect to LPS or media exposure, and IFN-γ rescue, but measured chymotrypsin-like, postacidic, and trypsin-like activities of proteasome (Fig. 5, A–C). Compared with media controls (MM), mainly chymotrypsin-like and trypsin-like activities were most significantly affected and upregulated by LPS treatment (ML) in both RAW and THP-1 cells (P <0.05) (Fig. 5, A and C). RAW cells (XYZ) had lower chymotrypsin-like and trypsin-like activities, as compared with THP-1 cells, because the latter cells contained LMP proteasome subunits. In contrast, RAW cells showed a higher postacidic activity (due to Y). Tolerance treatment of THP1 cells with LPS for 24 h (LM) resulted in significantly decreased chymotrypsin-like and trypsin-like activities compared with M, while decrease in postacidic activity was observed only in RAW cells (Fig. 5, A–C), but second LPS treatment for 4 h, in both RAW and THP1 cells (LL) significantly decreased chymotrypsin-like and trypsin-like activities. As observed with proteasome subunits, IFN-γ treatment followed by 4 h LPS exposure significantly increased chymotrypsin-like and trypsin-like activities in both cell lines; while only postacidic activity was revived only in RAW cells (P <0.05) (Fig. 5, A–C).
Furthermore, we carried out similar tolerance experiments with CD14+ human monocytes where MM group served as a control, and ML (first LPS treatment, mimicking an initial inflammatory response) showed a robust upregulation in levels of TNFα protein and mRNA after 4 h (435.5 fold increase in TNFα protein and 70.5 fold increase in TNFα mRNA δCT values) (P <0.05) as expected (Fig. 6, A and B). TNFα (protein and mRNA) expression levels were significantly reduced as compared with the ML group in tolerized cells LM and LL (P <0.05). Thus, initial LPS treatment induced a state of tolerance, demonstrated by reduced levels of TNFα mRNA on re-exposure to LPS in human monocytes. Similarly, when tolerized (LM) human monocytes were treated with IFN-γ and LPS, there was a concomitant increase in TNF-α protein and gene expression (P <0.05) (Fig. 6, A and B) ⋅ However, human monocytes (data not presented) did not produce detectable NO or inducible nitric oxide synthase (iNOS) in response to LPS, under any of the conditions tested, and LPS-induced tolerance on CD14+ human monocytes had no effect on mRNA of X, Y, and Z proteasome subunits (Fig. 6C). There was a significant increase in LMP subunit expression after 4 h LPS exposure (ML) especially (P <0.05) (Fig. 6D). Compared with non-tolerized cells (ML), LPS tolerized human monocytes (LL) differed markedly in that they failed to upregulate LMP subunit expression after re-exposure to LPS for 4 h, as observed with other cell lines. This failure to upregulate LMP subunit expression in CD14+ monocytes was partially rescued by IFN-γ treatment alone (P <0.05) (Fig. 6D). After IFN-γ and LPS treatment of tolerant cells (LM), there was a significant increase in LMP7, LMP2, and LMP10 gene expression (P <0.05) (Fig. 6D). Collectively, all subsets of cells that contained either X, Y, Z, or LMP subunits or both; induced TNF-α in response to LPS and developed tolerance and these cells could be rescued by IFN-γ or IFN-γ and LPS treatments in human monocytes.
We have established first that human monocyte/mouse macrophage heterogeneity and development can be strongly correlated to differences in proteasome structure/function (Fig. 7). Subunits X, Y, LMP7, and LMP2 were present in mouse macrophages, while subunits Z and LMP10 were not observed in significant levels in all cells described above. Simplistically, cells can now be classified into three major subtypes those containing either X, Y, Z; X, Y, Z, and LMP; or LMP subunits. Moreover, priming with thioglycollate (in vivo), PMA, or LPS reprograms subunits in primed cells from X, Y, Z, to LMPs in newly synthesized proteasomes of peritoneal murine macrophages, which consequently leads to changes in specificities of proteasome's proteases from postacidic to chymotrypsin-like and trypsin-like activities, thus affecting cytokine expression and NO levels. We selected cells containing: X, Y, Z subunits (unprimed RAW 264.7 cells); X, Y, Z, and LMP subunits (primed RAW 264.7 cells), or LMP subunits (human CD14+ monocytes, THP1 cells) for our studies. These cells differed in TNF-α and NO responses induced by LPS. While primed RAW 264.7 cells and murine macrophages containing X, Y, Z and LMP proteasome subunits induced robust levels of TNF-α and NO in response to LPS. Cells that contain only LMP subunits such as THP-1 and human monocytes, or X, Y, Z subunits (RAW 264.7 cells, not primed) induced TNF-α, but not, NO in response to LPS. Thus, suggesting that a combination of constitutive X, Y, Z and inducible subunits LMP in cells are important for efficient LPS-induced NO.
Secondly, we have identified for the first time that proteasome's proteases are upregulated (regardless of cell type) during inflammation (ML) and downregulated during tolerance in RAW 264.7, THP-1, and CD14+ monocytes (LM, LL). Treatment of RAW 264.7 macrophages with LPS (ML) results in induction of relatively high levels of gene expression of all X, Y, Z and LMP proteasome subunit genes that correlates with high TNF-α expression in cells. Then after second LPS treatment, there is downregulation of all proteases and TNF-α levels because cells become tolerant. Treatment with IFN-γ followed by LPS reverses their tolerant phenotype and cells are activated and new proteasome subunits are biosynthesized. In contrast, THP-1 and CD14+ human monocytes contained predominantly LMP subunits as compared with RAW 264.7 cells. Human CD14+ monocytes and THP1 cells do not perform all functions of macrophage and are not capable of inducing NO in response to LPS, but rather induced robust levels of TNF-α. Our data also revealed an upregulation of only LMP subunits, but not XYZ in response to LPS (cytokine induction), and this was followed by downregulation during LPS-induced tolerant human monocytes. This tolerance could be reversed by treatment with IFN-γ or IFN-γ+LPS which resulted in robust upregulation of proteasome's subunits/activities in monocytes. Thus, CD14+monocytes differed in their proteasome structures and function, as compared with mouse peritoneal macrophages.
Mechanistically, tolerance has been previously attributed to several proteins that block signaling, including TNF-α, interleukin-10 (IL-10), transforming growth factor-β (TGF-β), interleukin-1 receptor associated kinase (IRAK) M, (negative regulator of Toll signaling), IRAK1, IRAK-4, iNOS, suppressor of cytokine synthesis (SOCS) 1, SOCS3, (SH2-containingInositol 5′-Phosphatase) SHIP, and at the nuclear level, increase in p50/p50 homodimers, activation of peroxisome proliferator-activated receptor (PPAR)-γ, hypoxia-inducible factor (HIF)-1, and complex mechanism involving histone modification (acetylation, phosphorylation, and methylation) generating a histone code that produces docking sites for proteins regulating chromatin structure and gene transcription (25, 26). This topic on tolerance mechanisms has been recently reviewed by others and us (5, 27–31). Our model (Fig. 7) is consistent with most previous mechanisms of tolerance, because transcription/degradation of all cytokines and signaling proteins mentioned above is proteasome-dependent (12). Importantly, LPS-induced tolerance has been previously shown to be reversed in cells by IFNγ (32), and we suggest that this could be due to introduction of new proteasome LMP subunits in cells, which are primed and induce increased levels of cytokine expression in response to LPS.
Much of recent research on mechanisms of LPS-induced response has been centered on canonical pathway followed by activation of TLR4. Ubiquitin-proteasome pathway plays a pivotal role in LPS-induced signaling and can be envisioned as an on/off switch for inflammation/tolerance (6, 11). The cascade of signaling events that follow via MyD88 or TRIF/TRAM as the adapter proteins leads to the activation of NF-κB, via degradation of ubiquitinated and phosphorylated IκB by the proteasome. Similarly, we have shown that phosphorylation of ERK-1, JNK-1, and p38 (MAPK) is also proteasome dependent (10). Our data suggest that initial interaction of LPS with host macrophages induces the postacidic activity in RAW 264.7 cells, and then chymotrypsin-like, and trypsin-like activities in cells, initiating a process of proteasome-mediated degradation of signaling mediators such as TLR4, IRAK-1, IRAKM, phosphorylated interferon regulatory factor 3, TNF receptor associated factor (TRAF6), IκB-α, β, p105 degradation (responsible for biosynthesis of p50 subunits), and MAPK because of changes in proteasomal activities, proteasome subunits (priming, LMP mode), ubiquitination/deubiquitination and expression of proinflammatory cytokines (5, 11), This also leads to a net increase in ubiquitinated proteins and increased activation of transcription factors, such as NF-κB (33); however, HIF-1 (34), Keap/NRF2 (35), and PPAR-γ are inhibited following proteasome's activation. In contrast, during tolerance, very low proteasome subunit expression and activity leads to inhibition in NF-κB activation, but activation of HIF-1, PPAR-γ, and NrF2 transcription activities. Thus, the proteasome regulates the degradation of regulatory proteins and activities of transcription factors.
The proteasome has been shown to directly regulate the structure and function of chromatin and chromatin regulatory proteins (non-canonical pathway) (36). DNA and nuclear proteins histones (H2A, H2B, H3, and H4) form the nucleosomes that are present in chromatin. Post-translational modifications of histones such as acetylation, phosphorylation, methylation, ubiquitylation, and SUMOylation can affect the properties of chromatin to enhance or suppress gene transcription (36). The ubiquitin-proteasome pathway has been suggested to be involved in elongation phase of transcription to chromatin remodeling/modification (37); and also in protein degradation of unbound RNA polymerase II associated factor (38). Therefore, downregulation of proteasome's proteases can have a profound effect on gene expression via histone modification, chromatin remodeling, and RNA polymerase II associated factor.
Proteasome inhibitors such as lactacystin bind to the active site of proteasome subunit X and prevent the activation of CT-like activity and thus inhibit the transcription of both inflammatory and anti-inflammatory LPS-induced genes and >90% of the LPS-induced genes (total 800 genes) are proteasome-dependent (12). Although 5 μM lactacystin (specific for X, high doses 20 μM affects other subunits) and LMP7 knockdown was unable to completely inhibit the upregulation of TNF-α in response to LPS (14), it now appears that cells containing either X, Y, Z, or LMP type proteasomes can induce TNF-α expression; therefore, blocking one subunit may not be sufficient to inhibit TNF-α. Thus, proteasome inhibitors may be useful in alleviating the effects of agonist-induced early inflammation. We have shown that proteasome inhibitors and antibiotics can prevent LPS-induced septic shock in a cecal-ligation and puncture model. A selective inhibitor of LMP7 has been used to reduce arthritis in mice (39). Our present data indicate that proteasomes play a vital role in both inflammation and tolerance. These findings support the role of proteasome's protease-sites as potentially valuable immunotherapy targets in treatment of initial stages of sepsis, and other diseases in which excessive inflammation may play a key role, such as cancer, asthma, cardiac problems, irritable bowel syndrome, and autoimmune diseases (40, 41); whereas proteasome activators such as IFN-γ may be needed when the cells become tolerant during septic shock, or in immunocompromised individuals. These studies are vital for understanding function of proteasome's subunits during inflammation and tolerance in mouse and human cells, and for design of therapeutic strategies for all diseases based on inflammation.
The authors thank Dr David C. Morrison for helpful suggestions and Dr Stefanie Vogel for helpful discussions and critical review of the manuscript. The authors thank Xiu Qin Guan for excellent technical assistance with Western blots.
1. Pena OM, Hancock DG, Lyle NH, Linder A, Russell JA, Xia J, Fjell CD, Boyd JH, Hancock RE. An endotoxin tolerance signature predicts sepsis and organ dysfunction at initial clinical presentation. EBioMedicine
2014; 1 1:64–71.
2. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis
2013; 13 3:260–268.
3. Rajaiah R, Perkins DJ, Polumuri SK, Zhao A, Keegan AD, Vogel SN. Dissociation of endotoxin tolerance and differentiation of alternatively activated macrophages. J Immunol
2013; 190 9:4763–4772.
4. Shnyra A, Brewington R, Alipio A, Amura C, Morrison DC. Reprogramming of lipopolysaccharide-primed macrophages is controlled by a counterbalanced production of IL-10 and IL-12. J Immunol
1998; 160 8:3729–3736.
5. Rockwell CE, Morrison DC, Qureshi N. Lipid A-mediated tolerance and cancer therapy. Adv Exp Med Biol
6. Qureshi N, Morrison DC, Reis J. Proteasome protease mediated regulation of cytokine induction and inflammation. Biochim Biophys Acta
2012; 1823 11:2087–2093.
7. Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature
2007; 447 7147:972–978.
8. El Gazzar M, Yoza BK, Hu JY, Cousart SL, McCall CE. Epigenetic silencing of tumor necrosis factor alpha during endotoxin tolerance. J Biol Chem
2007; 282 37:26857–26864.
9. Medvedev AE, Sabroe I, Hasday JD, Vogel SN. Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J Endotoxin Res
2006; 12 3:133–150.
10. Qureshi N, Perera PY, Shen J, Zhang G, Lenschat A, Splitter G, Morrison DC, Vogel SN. The proteasome as a lipopolysaccharide-binding protein in macrophages: differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events. J Immunol
2003; 171 3:1515–1525.
11. Qureshi N, Vogel SN, Van Way C 3rd, Papasian CJ, Qureshi AA, Morrison DC. The proteasome: a central regulator of inflammation and macrophage function. Immunol Res
2005; 31 3:243–260.
12. Shen J, Reis J, Morrison DC, Papasian C, Raghavakaimal S, Kolbert C, Qureshi AA, Vogel SN, Qureshi N. Key inflammatory signaling pathways are regulated by the proteasome. Shock
2006; 25 5:472–484.
13. Reis J, Guan XQ, Kisselev AF, Papasian CJ, Qureshi AA, Morrison DC, Van Way CW 3rd, Vogel SN, Qureshi N. LPS-induced formation of immunoproteasomes: TNF-alpha and nitric oxide production are regulated by altered composition of proteasome-active sites. Cell Biochem Biophys
2011; 60 (1–2):77–88.
14. Reis J, Hassan F, Guan XQ, Shen J, Monaco JJ, Papasian CJ, Qureshi AA, Van Way CW 3rd, Vogel SN, Morrison DC, et al. The immunoproteasomes regulate LPS-induced TRIF/TRAM signaling pathway in murine macrophages. Cell Biochem Biophys
2011; 60 (1–2):119–126.
15. Rockwell CE, Qureshi N. Differential effects of lactacystin on cytokine production in activated Jurkat cells and murine splenocytes. Cytokine
2010; 51 1:12–17.
16. Hirsch C, Ploegh HL. Intracellular targeting of the proteasome. Trends Cell Biol
2000; 10 7:268–272.
17. Groettrup M, Khan S, Schwarz K, Schmidtke G. Interferon-gamma inducible exchanges of 20S proteasome active site subunits: why? Biochimie
2001; 83 (3–4):367–372.
18. Gaczynska M, Rock KL, Spies T, Goldberg AL. Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc Natl Acad Sci U S A
1994; 91 20:9213–9217.
19. Reis J, Tan X, Yang R, Rockwell CE, Papasian CJ, Vogel SN, Morrison DC, Qureshi AA, Qureshi N. A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model. Innate Immun
2008; 14 5:319–329.
20. Qureshi N, Takayama K, Mascagni P, Honovich J, Wong R, Cotter RJ. Complete structural determination of lipopolysaccharide obtained from deep rough mutant of Escherichia coli. Purification by high performance liquid chromatography and direct analysis by plasma desorption mass spectrometry. J Biol Chem
1988; 263 24:11971–11976.
21. Shen J, Gao JJ, Zhang G, Tan X, Morrison DC, Papasian C, Vogel SN, Qureshi N. Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation. Shock
2006; 25 6:594–599.
22. Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A
2015; 112 4:1167–1172.
23. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A
2013; 110 9:3507–3512.
24. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science
1998; 282 5396:2085–2088.
25. Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ. An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol
2007; 8 1:47–56.
26. Perkins DJ, Patel MC, Blanco JC, Vogel SN. Epigenetic mechanisms governing innate inflammatory responses. J Interferon Cytokine Res
2016; 36 7:454–461.
27. Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura A. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity
2002; 17 5:583–591.
28. van ’t Veer C, van den Pangaart PS, van Zoelen MA, de Kruif M, Birjmohun RS, Stroes ES, de Vos AF, van der Poll T. Induction of IRAK-M is associated with lipopolysaccharide tolerance in a human endotoxemia model. J Immunol
2007; 179 10:7110–7120.
29. Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN. Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol
2002; 169 9:5209–5216.
30. Chen J, Ivashkiv LB. IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc Natl Acad Sci U S A
2010; 107 45:19438–19443.
31. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol
2009; 30 10:475–487.
32. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature
2011; 472 7344:481–485.
33. Traenckner EB, Wilk S, Baeuerle PA. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. Embo J
1994; 13 22:5433–5441.
34. Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. Mol Cell Biol
2006; 26 15:5895–5907.
35. Sekhar KR, Yan XX, Freeman ML. Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene
2002; 21 44:6829–6834.
36. McCann TS, Tansey WP. Functions of the proteasome on chromatin. Biomolecules
2014; 4 4:1026–1044.
37. Kinyamu HK, Chen J, Archer TK. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J Mol Endocrinol
2005; 34 2:281–297.
38. Sun HY, Kim N, Hwang CS, Yoo JY. Protein degradation of RNA polymerase II-association factor 1(PAF1) is controlled by CNOT4 and 26S proteasome. PLoS One
2015; 10 5:e0125599.
39. Muchamuel T, Basler M, Aujay MA, Suzuki E, Kalim KW, Lauer C, Sylvain C, Ring ER, Shields J, Jiang J, et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med
2009; 15 7:781–787.
40. Schmidt N, Gonzalez E, Visekruna A, Kuhl AA, Loddenkemper C, Mollenkopf H, Kaufmann SH, Steinhoff U, Joeris T. Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut
2010; 59 7:896–906.
41. Verbrugge SE, Scheper RJ, Lems WF, de Gruijl TD, Jansen G. Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther
Keywords:© 2017 by the Shock Society
Cytokines; differentiation; endotoxin shock; inflammation; macrophages; proteasomes