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Cell injury/death leads to Increased pro-inflammatory mediators
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Endocytic lysosomal uptake leading to liver fibrosis||adjacent||High||Marina Kuburic (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages|
Key Event Relationship Description
Cell death, including both necrosis and apoptosis can lead toward inflammation. Faouzi and colleagues showed that apoptosis can induce hepatic inflammation equally as necrosis (Faouzi et al., 2001). Some studies indicate that phagocytes can produce inflammatory cytokines upon ingestion of apoptotic bodies (Uchimura et al., 1997).
When cells undergo necrosis they lose the integrity of their plasma membrane and release their intracellular contents, into the extracellular space. The same process can occur when apoptotic cells aren't cleared fast enough and their membrane becomes permeable to macromolecules, which presents secondary necrosis (Majno et al., 1995). There is evidence that the immune system has evolved the capacity to detect the release of intracellular molecules which stimulates the generation of adaptive immune responses to dying cells.
Intracellular content of dying cells that triggers immune response when excreted contains molecules named danger associated molecular patterns (DAMPs). DAMPs include for example HMGB-1, IL-1α, uric acid, DNA fragments, mitochondrial content, and ATP (Eigenbrod et al., 2008; Kono et al., 2010a; Sauter et al., 2000). DAMPs can be molecules that have non-inflammatory functions in living cells (such as HMGB-1, ATP) and acquire immunomodulatory properties when released (Rock and Kono, 2008), or alarmins, molecules that have cytokine-like properties (such as IL-1α, IL-6), which are stored in cells and released after cell lysis and contribute to the inflammatory response (Oppenheim and Yang, 2005; Vanden Berghe et al., 2006).
One of the most investigated DAMPs is HMGB-1 (Lotze et al., 2005). HMGB-1 is a nuclear protein that binds to chromatin and has a role in bending DNA and regulating gene transcription (Landsman et al., 1993). HMGB-1 is released by both necrotic and apoptotic cells (Scaffidi et al., 2002; Bell et al., 2006), but also apoptotic cells activate macrophages that engulf them to secrete HMGB-1 (Qin et al., 2006). This protein induces inflammation, dendritic cells maturation, migration, and T-cell activation (Scaffidi et al., 2002; Messmer et al., 2004; Rovere –Querini et al., 2004; Dumitriu et al., 2005; Yang et al., 2007).
HMGB-1 is a stimulus for tumour necrosis factor (TNF) synthesis and release, but it also significantly activates the synthesis of IL-1 α, IL-1 β, IL-1RA, IL-6, IL-8, MIP-1 a, and MIP-1 (Andersson et al., 2000). It was shown that HMGB-1 released from late apoptotic cells remains bound to nucleosomes and that HMGB1-nucleosome complexes activate antigen-presenting cells (APC) and induce secretion of cytokines by macrophages and expression of co-stimulatory molecules in DCs (Urbonaviciute et al., 2008).
HMGB-1 is not the only pro-inflammatory DAMP released from dying cells. Other DAMPs, S100A8/A9 and S100A12 proteins induce pro-inflammatory cytokine production by macrophages (Hofmann et al., 1999; Yang et al., 2001; Viemann et al., 2004; Ehlerman et al., 2006; Pouliot et al., 2008).
The adjuvant activity of cells was reduced by enzymatic depletion of uric acid, indicating that it is a major DAMP, at least in some cells (Shi et al., 2003). Uric acid is a mediator released from necrotic or apoptotic cells that has immunostimulatory properties in vivo (Gordon et al., 1985; Shi et al., 2003).
Insufficient autophagy of deteriorated mitochondria could lead to massive release of DAMPs such as mtDNA and possibly other mitochondrial proteins (Oka et al., 2012).
Receptors on host cells sense when DAMPs are released and that triggers the inflammatory process. These receptors are pattern-recognition receptors (PRRs) (Chen and Nunez, 2010). PRRs represent proteins by which cells recognize microbial entities, but also some of the host's own molecules and direct an immune response (Piccinini et al., 2010). PRRs can be broadly divided in five subfamilies: Toll-like receptors (TLRs), RIG-1-like receptors (RLRs), NOD like receptors (NLRs), AIM2-like receptors (ALRs) and C-type lectin receptors (CLRs) (Takeuchi and Akira, 2010; Wang et al., 2014). For example, HMGB-1 was reported to stimulate TLR2 and TLR4 (Park et al. 2004) and receptor for advanced glycation end products (RAGE) (Dumitriu et al., 2005), while NLRP3 has been involved in the inflammatory response to mono-sodium urate (MSU) (Martinon et al., 2006). Cellular nucleic acids can stimulate TLR7 and TLR9 on B cells to promote antibody responses (Green and Marshak-Rothstein, 2011; Leadbetter et al., 2002).
TLRs are placed either at the cell surface (TLR1, TLR2, TLR4, TLR5, and TLR6) or in the endolysosomal compartment (TLR3, TLR7, and TLR9) (Barton and Kagan, 2009). Upon binding with the ligand, they undergo a conformational change and initiate a signalling cascade via signal adaptor molecules: myeloid differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (MAL, also known as TIR-domain-containing adaptor protein; TIRAP), TIR domain-containing adaptor protein inducing interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM). MyD88 was essential for the inflammatory response to injected dead cells (Chen et al., 2007).
All TLRs, except TLR3, associate with MyD88, and this stimulates a kinase cascade resulting in the activation of mitogen activated protein kinases (MAPKs), c-Jun N-terminal kinases, p38, and extracellular signal–regulated kinases, and nuclear factor NF-kB (Akira and Takeda, 2004; Lee and Kim, 2007). NF-kB is an important transcription factor for IL -1β and NLRP3 (Wang et al., 2004; Bauernfeind et al., 2009).
NF-kB is a central mediator of pro-inflammatory gene induction and functions in both types of immune cells. NF-kB pathway is responsible for transcriptional induction of pro-inflammatory cytokines, chemokines and additional inflammatory mediators, such as NLRP3, pro-IL-1β and pro-IL-18 (Sun et al., 2013; Ghosh and Karin, 2002; Hayden and Ghosh, 2013).
Macrophages must first be ‘primed’ with a stimulus that induces the synthesis of pro-IL -1β and also upregulates the expression of NLRP3 (Bauernfeid et al., 2009; Franchi et al., 2009). The stimuli that can prime macrophages include TLR agonists and cytokines like TNF. When macrophages producing pro-IL -1β are stimulated with ATP or irritant particles, inactive pro-caspase 1 assembles into a molecular complex called the inflammasome and is cleaved into active form (Stutz et al., 2009; Schroder and Tschopp, 2010). Inflammasomes consist of caspase 1, apoptosis-associated speck-like protein containing CARD (ASC) and an NLRP (Schroder and Tschopp, 2010). The catalytically active caspase 1 then cleaves pro-IL-1β to its mature and active form (Stutz et al., 2009). Macrophages lacking any of the inflammasome components don't make mature IL-1 when stimulated in culture with sterile particles (Hornung et al., 2008; Halle et al., 2008). NF-κB signaling pathway is also involved in the regulation of inflammasome (Guo et al., 2015).
Sometimes substantial sterile inflammatory response can be seen in caspase 1-deficient mice (eg. Chen et al., 2007). This contrasts with the much more marked reduction of these responses that is consistently observed in IL-1β -deficient mice. These data imply that there must be a caspase 1-independent pathway for generating mature IL-1β in vivo (Dinarello, 2009).
In the sterile inflammatory response to cell death, the contribution of TNF appears to be more modest than IL-1 (Rock et al., 2011). A possible explanation might be that the IL-1 is being released from the dying cells themselves (Eigenbrod et al., 2008).
After engulfment of apoptotic bodies, Kupffer cells in liver express TNF, TNF-related apoptosis-inducing ligand (TRAIL), and Fas ligand (FasL) (Canbay et al. 2003), which can induce apoptosis in hepatocytes and further aggravate liver inflammation. Engulfment of apoptotic bodies by macrophages also induces FasL expression (Kiener et al., 1997), which is known to exert a pro-inflammatory activity (Chen et al., 1998).
Evidence Supporting this KER
The severity of cell death activation determines the outcome for the cell: inflammation is part of the tissue regeneration process, and intermediate apoptotic stimuli are able to trigger this response. Recruitment of inflammatory cells such as neutrophils is meant as a beneficial process, as for example apoptotic bodies of bacteria-infected cells can be removed. Thus the apoptotic cells can secrete soluble "find-me" factors that trigger infiltration of immune cells. However, if this becomes chronic it has the potential to enhance tissue damage and ultimately induce fibrosis (Jaeschke, 2002; Cullen et al., 2013).
Uncertainties and Inconsistencies
The inflammatory role of HMGB-1 is still not completely clear. There are many studies that confirm its pro-inflammatory activity. However, in some experiments highly purified HMGB-1 had little pro-inflammatory activity (Rouhiainen et al., 2007), while in another injection of recombinant HMGB-1 into infarcted heart muscle in vivo stimulated regeneration and repair (Limana et al., 2005).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Human (Andersson et al., 2000; Scaffidi et al., 2002; Bell et al., 2006; Clarke et al., 2010)
Mouse (Faouzi et al., 2001; Chen et al., 2007)
Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol (2004) 4: 499–511.
Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med (2000) 192:565–70.
Barton GM, Kagan JC. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol (2009) 9:535–542.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol (2009) 183: 787–791.
Bell CW, Jiang W, Reich CF, Pisetsky DS. The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol. (2006) 291(6): C1318–C1325.
Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF, Gores GJ. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology (2003) 38:1188–1198.
Chen JJ, Sun Y, Nabel GJ. Regulation of the proinflammatory effects of Fas ligand (CD95L). Science (1998) 282:1714–1717.
Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med (2007) 13:851–856.
Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. (2010) 10: 826–837.
Clarke MCH, Talib S, Fig NL, Bennet MR. Vascular Smooth Muscle Cell Apoptosis Induces Interleukin-1–Directed Inflammation, Effects of Hyperlipidemia-Mediated Inhibition of Phagocytosis. Circ Res. (2010) 106(2): 363–372.
Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. (2013) 49(6):1034-48.
Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol (2009) 27:519–550.
Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, Arnold B, Bianchi ME, Manfredi AA, and Rovere-Querini P.Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol (2005) 174:7506–7515.
Eigenbrod T, Park JH, Harder J, Iwakura Y, Nunez G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL- 1 alpha released from dying cells. J Immunol (2008) 181:8194–8198.
Ehlermann P, Eggers K, Bierhaus A, Most P, Weichenhan D, Greten J, Nawroth PP, Katus HA, Remppis A. Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products. Cardiovasc Diabetol (2006) 5: 6.
Faouzi S, Burckhardt BE, Hanson JC, Campe CB, Schrum LW, Rippe RA, Maher JJ. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-B-independent, caspase-3-dependent pathway. J Biol Chem (2001) 276:49077-49082.
Ferrari D, Chiozzi P, Falzoni S, Dal Suino M, Melchiorri L, Baricordi OR, Di Virgilio F. Extracellular ATP triggers IL- 1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol (1997) 159:1451–1458.
Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F. The P2X7 receptor: a key player in IL-1 processing and release. J Immunol (2006) 176:3877–3883.
Franchi L, Eigenbrod T, Nunez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. (2009) 183:792–796.
Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell (2002) 109: S81–S96.
Gordon TP, Kowanko IC, James M, Roberts-Thomson PJ. Monosodium urate crystal-induced prostaglandin synthesis in the rat subcutaneous air pouch. Clin Exp Rheumatol. (1985) 3:291–6.
Green NM, Marshak-Rothstein A. Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol (2011) 23:106–112.
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med (2015) 21: 677–687.
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol (2008) 9:857– 865.
Hayden MS, Ghosh S. NF-kappaB in immunobiology. Cell Res (2011) 21: 223–244.
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell (1999) 97:889–901.
Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol (2008) 9:847–856.
Imaeda AB, Watanabe A, Sohail MA, Mahmoud S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest (2009) 119:305–314.
Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin, Flavell RA, Leemans JC, Sutterwalaa FS. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci USA (2009) 106:20388–20393.
Jaeschke H. Inflammation in response to hepatocellular apoptosis. Hepatology. (2002) 35(4):964-966.
Kiener PA, Davis PM, Starling GC, Mehlin C, Klebanoff SJ, Ledbetter JA, Liles WC. Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages. J Exp Med (1997) 185:1511–1516.
Kono H, Chen CJ, Ontiveros F, Rock KL. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest (2010) 120:1939–1949.
Kono H, Karmarkar D, Iwakura Y, Rock KL. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J Immunol (2010) 184(8):4470-8.
Landsman D, Bustin M. A signature for the HMG-1 box DNA-binding proteins. Bioessays. (1993) 15:539–46.
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak- Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature (2002) 416:603– 607.
Lee MS, Kim YJ. Signaling pathways downstream of patternrecognition receptors and their cross talk. Annu Rev Biochem (2007) 76: 447–480.
Li J, Wang H, Mason JM, Levine J, Yu M, Ulloa L, Czura CJ, Tracey KJ, Yang H. Recombinant HMGB1 with cytokine-stimulating activity. J Immunol Methods. (2004) 289:211–23.
Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, Müller S, Pompilio G, Anversa P, Bianchi ME, Capogrossi MC. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res. (2005) 97(8): e73–e83
Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. (2005) 5:331–42.
Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol (1995) 146:3-15.
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. (2006) 440:237–41.
McDonald B, Pittman Keir, Menezes GB, Hirota SA, Slaba I, Waterhouse CCM, Beck PL, Muruve DA, Kubes P. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science( 2010) 330:362–366.
Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, Tracey KJ, and Chiorazzi N. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and TH1 polarization. J Immunol (2004) 173: 307–313.
Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med. (2000) 191:303–312.
Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature (2012) 485: 251–255.
Oppenheim JJ, Yang D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. (2005) 17, 359–365.
Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. (2004) 279:7370–7377.
Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm (2010) 21 Article ID 672395.
Pouliot P, Plante I, Raquil MA, Tessier PA, Olivier M. Myeloidrelated proteins rapidly modulate macrophage nitric oxide production during innate immune response. J Immunol (2008) 181: 3595–3601.
Qin S, Wang H, Yuan R, Li H, Ochani M, Ochani K, Rosas-Ballina M, Czura CJ, Huston JM, Miller E, Lin X, Sherry B, Kumar A, LaRosa G, Newman W, Tracey KJ, Yang H. Role of HMGB1 in apoptosis-mediated sepsis lethality. The Journal of Experimental Medicine. (2006) 203(7):1637-1642.
Rock KL, Kono H. The inflammatory response to cell death. Annual review of pathology. (2008) 3:99-126.
Rock KL, Lai JJ, Kono H. Innate and adaptive immune responses to cell death. Immunol Rev. (2011) 243(1): 191–205.
Rouhiainen A, Tumova S, Valmu L, Kalkkinen N, Rauvala H. Analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J Leukoc Biol. (2007) 81:49–58.
Rovere-Querini P, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, Dumitriu IE, Müller S, Iannacone M, Traversari C, Bianchi ME, Manfredi AA. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep (2004) 5:825–30.
Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. (2000) 191, 423–434.
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. (2002) 418:191–5.
Schroder K, Tschopp J. The inflammasomes. Cell (2010) 140:821–832.
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. (2003) 425:516–21.
Stutz A, Golenbock DT, Latz E. Inflammasomes: too big to miss. J Clin Invest (2009) 119:3502–3511.
Sun SC, Chang JH, Jin J. Regulation of nuclear factor-kappaB in autoimmunity. Trends Immunol (2013) 34: 282–289.
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell (2010) 140: 805–820.
Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemiareperfusion. J Exp Med. (2005) 201(7): 1135–1143.
Uchimura, E., Kodaira, T., Kurosaka, K., Yang, D., Watanabe, N., and Kobayashi, Y. Biochem. Biophys. Res. Commun. (1997) 239, 799–803.
Urbonaviciute V, Furnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME, Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann M, Voll RE. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med (2008) 205: 3007–3018.
Vanden Berghe T, Kalai M, Denecker G, Meeus A, Saelens X, Vandenabeele P. Necrosis is associated with IL-6 production but apoptosis is not. Cell. Signal. (2006) 18: 328–335.
Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, Hirono K, Ichida F, Foell D, Kehrel B, Gerke V, Sorg C, Roth J. Myeloid-related protein 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood (2004) 105: 2955–2962.
Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med (2004) 255: 320–331.
Wang JQ, Jeelall YS, Ferguson LL, Horikawa K. Toll-Like Receptors and Cancer: MYD88 Mutation and Inflammation. Front Immunol. (2014) 5: 367.
Yang Z, Tao T, Raftery MJ, Youssef P, Di Girolamo N, Geczy CL. Proinflammatory properties of the human S100 protein S100A12. J Leukoc Biol (2001) 69: 986–994.
Yang D, Chen Q, Yang H, Tracey KJ, Bustin M, Oppenheim JJ. High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol (2007) 81: 59–66.
Zimmermann K, Volkel D, Pable S, Lindner T, Kramberger F, Bahrami S, Scheiflinger F. Native versus recombinant high-mobility group B1 proteins: functional activity in vitro. Inflammation. (2004) 28:221–9.