A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases

“, T helper 1 (Th1) cells, Th2 cells, and Th17 cells, which produce IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may init…”

“…Th2 cells, and Th17 cells, which produce IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may initiate…”

“…which produce IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may initiate and drive the…”

“…IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may initiate and drive the progression of disease.”

“…1 (Th1) cells, Th2 cells, and Th17 cells, which produce IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al.,…”

“They might also induce IL-6 and/or CCL20 expression based on the fact that DAMPs can activate the NF-κB pathway (Bianchi, 2007; Sims et al., 2010).”

“Furthermore, activated CD4+ T cells are known to express TNFα (Cherwinski et al., 1987; Constant and Bottomly, 1997; Brennan et al., 2002; Williams et al., 2008), while we have found a lack of TNFα attenuates arthritis in F759 mice (unpublished data).”

“They might also induce IL-6 and/or CCL20 expression based on the fact that DAMPs can activate the NF-κB pathway (Bianchi, 2007; Sims et al., 2010).”

“In support of this idea, numerous studies have demonstrated the efficacy of targeting TNFα when treating RA and other chronic autoimmune diseases, the majority of which involve class II MHC molecules (Feldmann and Maini, 2001).”

“Furthermore, activated CD4+ T cells are known to express TNFα (Cherwinski et al., 1987; Constant and Bottomly, 1997; Brennan et al., 2002; Williams et al., 2008), while we have found a lack of TNFα attenuates arthritis in F759 mice (unpublished data).”

“…diseases might be associated with various genetic aberrations including a somatic mutation in gp130 molecules that induces STAT3 hyperactivation, and mutations in NF-κB and its regulators that lead to dysregualted NF-κB signaling (Lenz et al., 2008; Compagno et al., 2009; Rebouissou et al., 2009).”

“Nevertheless, there still remains evidence that STAT3 abnormalities are involved, as demonstrated in the B cells of patients with hyper-immunoglobulin E syndrome (Minegishi et al., 2007).”

“…diseases might be associated with various genetic aberrations including a somatic mutation in gp130 molecules that induces STAT3 hyperactivation, and mutations in NF-κB and its regulators that lead to dysregualted NF-κB signaling (Lenz et al., 2008; Compagno et al., 2009; Rebouissou et al., 2009).”

“Instead, it may be the consequence of local events that are initiated by inflammation triggered by certain genetic and/or environmental factors (Hirano, 1998, 2010; Matsumoto et al., 1999; Marrack et al., 2001; Sawa et al., 2006) such that the specificity of an autoimmune disease could be…”

“Moreover, patients with RA show high synovial concentrations of IL-6 (Hirano et al., 1988), while anti-IL-6 receptor therapy is effective for some RA patients (Nakagawa et al., 2010).”

“This could help explain the occurrence of other diseases too, as the homeostatic proliferation of CD4+ T cells has been shown to be involved in the development of diabetes, arthritis, and Omenn syndrome (King et al., 2004; Jang et al., 2006; Sawa et al., 2006; Khiong et al., 2007).”

“To date, 10 IL-6 family cytokines have been identified: IL-6, oncostatin M, LIF, CNTF, CT-1, NNT-1, neuropoietin, IL-11, IL-27, and IL-31 (Kamimura et al., 2003; Murakami et al., 2004; Suthaus et al., 2010).”

“Instead, it may be the consequence of local events that are initiated by inflammation triggered by certain genetic and/or environmental factors (Hirano, 1998, 2010; Matsumoto et al., 1999; Marrack et al., 2001; Sawa et al., 2006) such that the specificity of an autoimmune disease could be determined by the non-immune…”

“…diseases like rheumatoid arthritis (RA) develop in specific tissues as a result of cognate antigen-recognition by CD4+ T cells, particularly when these diseases are associated with class II major histocompatibility complex (MHC) alleles (Steinman, 2001; Zhang et al., 2008; Imboden, 2009).”

“…JAK–signal transducer and activator of transcription 3 (STAT3) pathway, which is mediated by the YxxQ motif of gp130, and the SHP2–Gab-Ras-Erk–MAPK pathway, which is regulated by Y759, a cytoplasmic SOCS3 binding residue in gp130 (Fukada et al., 1996; Ohtani et al., 2000; Kamimura et al., 2003).”

“…CD4+ T cells – e.g., T helper 1 (Th1) cells, Th2 cells, and Th17 cells, which produce IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al.,…”

“jp It is commonly thought that autoimmune diseases are caused by the breakdown of selftolerance, which suggests the recognition of specific antigens by autoreactive CD4+ T cells contribute to the specificity of autoimmune diseases (Marrack et al., 2001; Mathis and Benoist, 2004).”

“chronic inflammations in tissue-specific MHC class”

“…IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may initiate and drive the progression of disease.”

“The number of cytokine-secreting effector/memory CD4+ T cells increases with age due to an accumulation of pathogen-specific memory T cells and homeostatic proliferation of CD4+ T cells.”

“…diseases might be associated with various genetic aberrations including a somatic mutation in gp130 molecules that induces STAT3 hyperactivation, and mutations in NF-κB and its regulators that lead to dysregualted NF-κB signaling (Lenz et al., 2008; Compagno et al., 2009; Rebouissou et al., 2009).”

“Consistent with this, autoimmune diseases are sometimes induced after infections that also increase the number of activated, pathogen-specific, cytokine-secreting CD4+ T cells (Kivity et al., 2009).”

“For instance, HTLV1 infection is a significant risk factor for arthritis (Ishihara et al., 2004), while the transgenic expression of p40 Tax, a product of HTLV1 that activates NF-κB, causes a RA-like disease in mice (Iwakura et al., 1991).”

“In several cases, however, even for diseases associated with class II major histocompatibility complex (MHC) alleles, the causative tissue-specific antigens recognized by memory/activated CD4+ T cells have not been established (Mocci et al., 2000; Skapenko et al., 2005).”

“The F759 knock-in mouse line (F759), for example, which expresses a mutant variant of gp130 where Y759 is substituted for phenylalanine (F), shows enhanced IL-6-mediated STAT3 activation due to a lack of SOCS3-mediated suppression (Ohtani et al., 2000).”

“…IFNγ, IL-4, and IL-17A, respectively (Mosmann and Coffman, 1989; Glimcher and Murphy, 2000; Cua et al., 2003; Harrington et al., 2005; Park et al., 2005; Veldhoen et al., 2006; Zhu et al., 2006; Bettelli et al., 2007; Nishihara et al., 2007) – may initiate and drive the progression of disease.”

“Consistent with this notion, SOCS3 deficiency in liver cells increased the degree of liver fibrosis (Ogata et al., 2006).”

“Additionally, a number of studies have suggested IL-6 has an important role in autoimmune diseases (Hirano, 1998, 2010; O’Shea et al., 2002; Sakaguchi and Sakaguchi, 2005; Awasthi and Kuchroo, 2009).”

“Consistent with this, these diseases are more prevalent in older patients who have a larger population of memory/activated CD4+ T cells, some of which secrete cytokines because of homeostatic proliferation and/or chronic inflammations in other tissues (Hasler and Zouali, 2005; Larbi et al., 2008).”

“As these mice age, they spontaneously develop a RA-like tissue-specific disease, indicating that constitutive activation of IL-6 signaling is involved in the development of certain autoimmune diseases (Atsumi et al., 2002).”

“…diseases like rheumatoid arthritis (RA) develop in specific tissues as a result of cognate antigen-recognition by CD4+ T cells, particularly when these diseases are associated with class II major histocompatibility complex (MHC) alleles (Steinman, 2001; Zhang et al., 2008; Imboden, 2009).”

“TISSUE-SPECIFIC MHC CLASS II-ASSOCIATED AUTOIMMUNE DISEASES AND ANTIGEN-RECOGNITIONS BY CD4+ T CELLS It has been proposed that autoimmune diseases are caused by a breakdown of self-tolerance due to multiple genetic and/or environmental factors (Marrack et al., 2001; Mathis and Benoist, 2004), suggesting the dysregulat…”

“chronic inflammations in tissue-specific MHC class”

“Regarding the development of arthritis in F759 mice, it is not only the immune system, but also non-immune tissue that are involved, indicating that the importance of their interactions (Sawa et al., 2006, 2009; Ogura et al., 2008; Hirano, 2010; Murakami et al., 2011).”

“Furthermore, activated CD4+ T cells are known to express TNFα (Cherwinski et al., 1987; Constant and Bottomly, 1997; Brennan et al., 2002; Williams et al., 2008), while we have found a lack of TNFα attenuates arthritis in F759 mice (unpublished data).”

“This process is also associated with a specific cytokine profile that includes the IL-17A and IFNγ produced by CD4+ T cells (Gudmundsdottir and Turka, 2001; Khiong et al., 2007; Nishihara et al., 2007).”

“…peptides such as derivatives of aggrecan, fibrillin, and collagen have been identified in humans (Polgár et al., 2003; Chapuy-Regaud et al., 2005; Takizawa et al., 2006; Van Steendam et al., 2010), while immunodominant MHC class II peptides in an animal model have been found to match those seen…”

“MINI REVIEW ARTICLE published: 16 June 2011 doi: 10.3389/fimmu.2011.00022”

“…may also contribute to class II MHCassociated diseases by enhancing IL-6 signaling in affected tissues and cells like type 1 collagen+ cells (the fourth step), as nonpolarized activated CD4+ T cells, Th1, and IL-17A−/− Th17 cells too induce a mild form of arthritis in F759 mice (Murakami et…”

“chronic inflammations in tissue-specific MHC class”

“Consistent with this, these diseases are more prevalent in older patients who have a larger population of memory/activated CD4+ T cells, some of which secrete cytokines because of homeostatic proliferation and/or chronic inflammations in other tissues (Hasler and Zouali, 2005; Larbi et al., 2008).”

“This could help explain the occurrence of other diseases too, as the homeostatic proliferation of CD4+ T cells has been shown to be involved in the development of diabetes, arthritis, and Omenn syndrome (King et al., 2004; Jang et al., 2006; Sawa et al., 2006; Khiong et al., 2007).”

“Moreover, patients with RA show high synovial concentrations of IL-6 (Hirano et al., 1988), while anti-IL-6 receptor therapy is effective for some RA patients (Nakagawa et al., 2010).”

“Consistent with this, joint-specific antigenic peptides such as derivatives of aggrecan, fibrillin, and collagen have been identified in humans (Polgár et al., 2003; Chapuy-Regaud et al., 2005; Takizawa et al., 2006; Van Steendam et al., 2010), while immunodominant MHC class II peptides in an…”

“To date, 10 IL-6 family cytokines have been identified: IL-6, oncostatin M, LIF, CNTF, CT-1, NNT-1, neuropoietin, IL-11, IL-27, and IL-31 (Kamimura et al., 2003; Murakami et al., 2004; Suthaus et al., 2010).”

“To date, 10 IL-6 family cytokines have been identified: IL-6, oncostatin M, LIF, CNTF, CT-1, NNT-1, neuropoietin, IL-11, IL-27, and IL-31 (Kamimura et al., 2003; Murakami et al., 2004; Suthaus et al., 2010).”

“Additionally, a number of studies have suggested IL-6 has an important role in autoimmune diseases (Hirano, 1998, 2010; O’Shea et al., 2002; Sakaguchi and Sakaguchi, 2005; Awasthi and Kuchroo, 2009).”

“Moreover, many viral proteins, including the hepatitis C virus Core protein and EBNA2 from the Epstein–Barr virus, are strong STAT3 activators (Yoshida et al., 2002; Muromoto et al., 2009).”

“This could help explain the occurrence of other diseases too, as the homeostatic proliferation of CD4+ T cells has been shown to be involved in the development of diabetes, arthritis, and Omenn syndrome (King et al., 2004; Jang et al., 2006; Sawa et al., 2006; Khiong et al., 2007).”

“Moreover, it is interesting that LPS administration around the joints induces arthritis in mice that have an excess number of Th1 cells (Nickdel et al., 2009).”

“…triggered by certain genetic and/or environmental factors (Hirano, 1998, 2010; Matsumoto et al., 1999; Marrack et al., 2001; Sawa et al., 2006) such that the specificity of an autoimmune disease could be determined by the non-immune target tissue itself (Brennan et al., 2002; Hirano, 2002).”

“Rheumatoid arthritis (RA) and arthritis in F759 knock-in mice (F759 mice) are such examples (Atsumi et al., 2002; Brennan et al., 2002; Falgarone et al., 2009).”

“In several cases, however, even for diseases associated with class II major histocompatibility complex (MHC) alleles, the causative tissue-specific antigens recognized by memory/activated CD4+ T cells have not been established (Mocci et al., 2000; Skapenko et al., 2005).”

“The number of cytokine-secreting effector/memory CD4+ T cells increases with age due to an accumulation of pathogen-specific memory T cells and homeostatic proliferation of CD4+ T cells.”

“MINI REVIEW ARTICLE published: 16 June 2011 doi: 10.3389/fimmu.2011.00022”

“This view highlights the importance of local initiators in the target tissue as a trigger of auto-immunity (49, 51, 52, 57, 232).”

“…of the antigen-specificity, (2) triggering factors for local accumulation of CD4+ T cells, (3) transient activation of the IL-6 amplifier in local tissues by cytokines from the CD4+ T cells, and (4) increased sensitivity to the cytokines in these local tissues (Murakami and Hirano, 2011).”

“In vivo and in vitro experiments have shown that the IL-6 amplifier is activated by simultaneous activation of NFκB and STAT3 and that it locally induces chemokines for inflammation [22].”

“In this system, massive chemokine expression caused by the simultaneous stimulation of NFkB and STAT3 is followed by disruption of local homeostasis due to the local accumulation of various immune cells ( Murakami and Hirano, 2011 ; Murakami et al., 2011 ; Lee et al., 2012 , 2013 ).”

“This may be due to reported reductions in IL-17 with chronic exercise, which would interfere with expression of IL-17dependent upregulation of chemokines (Murakami and Hirano, 2011).”

“This process, in which STAT3 and NF-κB are simultaneously activated, is called “IL-6 amplifier” [73] and it is well studied in other pathological conditions, such as major histocompatibility complex (MHC) class II-associated autoimmune diseases [76] and transplantation rejection [77,78].”

“104,105 Tfh can further assist B cells in promoting antibody production.”

“From these studies, a fourstep model was proposed that explains the mechanism for tissue specific autoimmune diseases by antigen-non-specific activation of the IL-6 amplifier.(22) This intriguing model is based on the experiments utilising artificial manipulations, such as neonatal thymectomy,(18) puncture or injectio…”

“We discovered chemokine/IL-6–inducing machinery, the inflammation amplifier (formerly the IL-6 amplifier), as a regulator of chronic inflammation in nonimmune cells, such as endothelial cells and fibroblasts (1, 2).”

“A major effect of IL-17A was to enhance IL-6 production (Murakami & Hirano, 2011; Kurosu et al, 2023), which links the cytokine-level event to the effector-level event, such as vascular leakage and subsequent organ failure.”

“This indicates that CD4+ T cell-derived cytokines such as IL-17A may lead to sustained activation of IL-6 due to T-cell activation and local accumulation that are not related to antigen specificity (51).”

“87 In this context, our findings suggest that Ras V12 / scrib tumors co-opt this conserved cytokine amplification mechanism, which is normally activated during infection, tissue repair, and regeneration, to accelerate their own growth.”

“The crosstalk between the JAK-STAT3 and IκB-NFκB pathways promotes the production of IL6 and provides positive feedback for IL6 signaling [55, 56].”

“…multisystemic symptoms caused by chronic nasopharyngitis may be triggered by persistent neural stimulation activating the inflammatory circuit (IL-6 amplifier) [30] in the brainstem and hypothalamic vessels, thereby promoting the central invasion of autoreactive T cells via the gateway reflex [31].”

“13,31 In synovial tissue, IL-6/STAT3 signaling path - way is involved in the activation of SFs and in turn induces the ex - pression of IL-6, establishing an autocrine loop that causes further STAT3 activation and initiation of inflammatory and destructive processes in RA.”

“Studies have shown that the transcription factor STAT-3 plays a critical role in the development of Th17 cells (Mori et al. 2011; Murakami and Hirano 2011; Sawa et al. 2006; Shouda et al. 2001; Yang et al. 2007).”

“key molecular mechanism in chronic inflammation (15, 52, 53), which triggers a vicious circle of escalating RA disease activity (51, 54, 55).”

“Inhibition of HDAC3 by VPA results in phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3), a molecule that afterward translocates to the cell nucleus and activates the transcription of genes which are implicated in a wide range of biological processes, including induction of immune response,…”

“This accumulation of activated CD4+ T cells and other immune cells raises the levels of various cytokines, such as IL−17A, TNF-α, and IL−6, further activating the NF-κB and STAT3 pathways in synovial fibroblasts, chondrocytes, and endothelial cells [2,16,27,28].”