I wonder if IL-10 is what the upcoming article will be about?
There was a massive increase in IL-10 on the 5 patients listed in the NEJM article
<<these studies indicate that resolution of infection requires a coordinated response in which initial proinflammatory mechanisms clear the pathogen and are then down-modulated by IL-10 before pathology occurs. Thus, the timing as well as the relative amounts of proinflammatory and anti-inflammatory cytokine production are critical for safe resolution of infection.
IL-10: The Master Regulator of Immunity to Infection
Kevin N. Couper, Daniel G. Blount and Eleanor M. Riley
J Immunol May 1, 2008, 180 (9) 5771-5777; DOI: https://doi.org/10.4049/jimmunol.180.9.5771
ArticleFigures & DataInfo & Metrics PDF
Abstract
IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen clearance and ameliorate immunopathology. Many different types of cells can produce IL-10, with the major source of IL-10 varying in different tissues or during acute or chronic stages of the same infection. The priming of these various IL-10-producing populations during infections is not well understood and it is not clear whether the cellular source of IL-10 during infection dictates its cellular target and thus its outcome. In this article we review the biology of IL-10, its cellular sources, and its role in viral, bacterial, and protozoal infections.
It is widely appreciated that many of the severe complications of infection result from excessive immune activation. Therapeutic and preventive strategies to augment immune-mediated clearance of pathogens and infected host cells have, on occasion, directly exacerbated tissue damage and increased mortality (1, 2, 3). These studies demonstrate that maximal pathogen control does not necessarily lead to minimal disease and highlight the essential role for immunoregulatory components of the immune response in limiting pathology.
First described as a product of Th2 cells that inhibited cytokine synthesis in Th1 cells (4), IL-10 is now known to be produced by macrophages, dendritic cells (DC),3 B cells, and various subsets of CD4+ and CD8+ T cells (5, 6). Initially shown to regulate T cell responses, many of the effects of IL-10 on T cell and NK cell function are now known to be indirect, being mediated via a direct effect of IL-10 on monocyte-macrophages. Thus, IL-10 inhibits MHC class II and costimulatory molecule B7-1/B7-2 expression on monocytes and macrophages and limits the production of proinflammatory cytokines (including IL-1α and β, IL-6, IL-12, IL-18, and TNF-α) and chemokines (MCP1, MCP5, RANTES, IL-8, IP-10, and MIP-2) (reviewed in Ref. 5). Importantly, autocrine IL-10 signaling in DC can inhibit chemokine production and prevent their trafficking to lymph nodes as shown in mycobacterial infection, leading to the failure to recruit and induce Th1 differentiation of naive T cells (7). Nevertheless, IL-10 can act directly on CD4+ T cells, inhibiting proliferation and production of IL-2, IFN-γ, IL-4, IL-5 and TNF-α (5, 8, 9). Thus, IL-10 can directly regulate innate and adaptive Th1 and Th2 responses by limiting T cell activation and differentiation in the lymph nodes as well as suppressing proinflammatory responses in tissues, leading to impaired pathogen control and/or reduced immunopathology.
The role of IL-10 during infection
IL-10 has emerged as a key immunoregulator during infection with viruses, bacteria, fungi, protozoa, and helminths (Table I⇓), ameliorating the excessive Th1 and CD8+ T cell responses (typified by overproduction of IFN-γ and TNF-α) that are responsible for much of the immunopathology associated with infections including Toxoplasma gondii (1, 10), Trypanosoma spp. (2, 11), Plasmodium spp. (12, 13), Mycobacterium spp. (14), and HSV (15). Thus, as summarized in Table I⇓, ablation of IL-10 signaling results in the onset of severe, often fatal immunopathology in a number of infections including T. gondii (1, 10), malaria (3, 16, 17), and Trypanosoma cruzi (2). IL-10 by itself and through cooperation with Th1 cytokines (such as IL-12) also regulates Th2 responses (8, 9, 18, 19, 20) to prevent the overproduction of IL-4, IL-5 and IL-13, cytokines that can lead to severe fibrosis in, for example, Schistosoma mansoni (reviewed in Ref. 21), hepatitis C virus (22), and mycobacterial (23) infections. Amelioration of the allergic Th2 responses that can accompany helminth infections also depends on the induction of IL-10 (24). Nevertheless, excessive or mistimed IL-10 production can inhibit the proinflammatory response to Plasmodium spp. (25, 26), Leishmania spp. (27, 28, 29), T. cruzi (30), Mycobacterium spp. (31), and lymphocytic choriomeningitis virus (32, 33) to the extent that pathogens escape immune control, resulting in either fulminant and rapidly fatal or chronic nonhealing infections. For example, during Mycobacterium avium infection very early IL-10 production in BALB/c but not C57BL/6 mice is correlated with the failure of BALB/c mice to control the infection; ablation of IL-10 signaling led to enhanced pathogen control in BALB/c but not C57BL/6 mice, demonstrating the causal relationship between IL-10 and the lack of pathogen control (31). Similarly, in other infections where production of IL-10 correlates with poor pathogen control, experimental ablation of IL-10 or inhibition of IL-10 signaling restores pathogen control and reduces the severity of disease, thereby establishing a direct correlation between inappropriate IL-10 production and disease severity. Conversely, ablation of IL-10 signaling during normally benign infections may augment proinflammatory responses, enhancing pathogen control at the considerable cost of more severe immunopathology (1, 2, 3, 17, 34). However, it is often not clear whether high concentrations of IL-10 during virulent infections are a cause or a consequence of high pathogen burdens. In the former case, IL-10 would directly inhibit pathogen clearance (and may be induced by the pathogen to promote its own survival). Thus, transgenic overexpression of IL-10 (under control of the MHC II promoter) in APC leads to uncontrolled pathogen growth in Leishmania major, Listeria monocytogenes, and M. avium infections (35, 36). In the latter case for example, where the pathogen is able to resist clearance by normally effective mechanisms, IL-10 may be produced to reduce inflammation and thereby minimize pathology. For instance, during virulent infection with the SD strain of L. major, high pathogen loads drive excessive Th1 responses (27) and these, in turn, promote the development of self-limiting adaptive IL-10-producing T cells that dampen down Th1 responses, (28, 37), establishing a positive feedback loop whereby T cell-derived IL-10 further inhibits anti-microbial immune responses, allowing fulminant and inevitably fatal infections to develop. In such cases, IL-10 concentrations often “track” pathogen burdens and systemic IFN-γ concentrations (25, 27, 38).
https://www.jimmunol.org/content/180/9/5771
There was a massive increase in IL-10 on the 5 patients listed in the NEJM article
<<these studies indicate that resolution of infection requires a coordinated response in which initial proinflammatory mechanisms clear the pathogen and are then down-modulated by IL-10 before pathology occurs. Thus, the timing as well as the relative amounts of proinflammatory and anti-inflammatory cytokine production are critical for safe resolution of infection.
IL-10: The Master Regulator of Immunity to Infection
Kevin N. Couper, Daniel G. Blount and Eleanor M. Riley
J Immunol May 1, 2008, 180 (9) 5771-5777; DOI: https://doi.org/10.4049/jimmunol.180.9.5771
ArticleFigures & DataInfo & Metrics PDF
Abstract
IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen clearance and ameliorate immunopathology. Many different types of cells can produce IL-10, with the major source of IL-10 varying in different tissues or during acute or chronic stages of the same infection. The priming of these various IL-10-producing populations during infections is not well understood and it is not clear whether the cellular source of IL-10 during infection dictates its cellular target and thus its outcome. In this article we review the biology of IL-10, its cellular sources, and its role in viral, bacterial, and protozoal infections.
It is widely appreciated that many of the severe complications of infection result from excessive immune activation. Therapeutic and preventive strategies to augment immune-mediated clearance of pathogens and infected host cells have, on occasion, directly exacerbated tissue damage and increased mortality (1, 2, 3). These studies demonstrate that maximal pathogen control does not necessarily lead to minimal disease and highlight the essential role for immunoregulatory components of the immune response in limiting pathology.
First described as a product of Th2 cells that inhibited cytokine synthesis in Th1 cells (4), IL-10 is now known to be produced by macrophages, dendritic cells (DC),3 B cells, and various subsets of CD4+ and CD8+ T cells (5, 6). Initially shown to regulate T cell responses, many of the effects of IL-10 on T cell and NK cell function are now known to be indirect, being mediated via a direct effect of IL-10 on monocyte-macrophages. Thus, IL-10 inhibits MHC class II and costimulatory molecule B7-1/B7-2 expression on monocytes and macrophages and limits the production of proinflammatory cytokines (including IL-1α and β, IL-6, IL-12, IL-18, and TNF-α) and chemokines (MCP1, MCP5, RANTES, IL-8, IP-10, and MIP-2) (reviewed in Ref. 5). Importantly, autocrine IL-10 signaling in DC can inhibit chemokine production and prevent their trafficking to lymph nodes as shown in mycobacterial infection, leading to the failure to recruit and induce Th1 differentiation of naive T cells (7). Nevertheless, IL-10 can act directly on CD4+ T cells, inhibiting proliferation and production of IL-2, IFN-γ, IL-4, IL-5 and TNF-α (5, 8, 9). Thus, IL-10 can directly regulate innate and adaptive Th1 and Th2 responses by limiting T cell activation and differentiation in the lymph nodes as well as suppressing proinflammatory responses in tissues, leading to impaired pathogen control and/or reduced immunopathology.
The role of IL-10 during infection
IL-10 has emerged as a key immunoregulator during infection with viruses, bacteria, fungi, protozoa, and helminths (Table I⇓), ameliorating the excessive Th1 and CD8+ T cell responses (typified by overproduction of IFN-γ and TNF-α) that are responsible for much of the immunopathology associated with infections including Toxoplasma gondii (1, 10), Trypanosoma spp. (2, 11), Plasmodium spp. (12, 13), Mycobacterium spp. (14), and HSV (15). Thus, as summarized in Table I⇓, ablation of IL-10 signaling results in the onset of severe, often fatal immunopathology in a number of infections including T. gondii (1, 10), malaria (3, 16, 17), and Trypanosoma cruzi (2). IL-10 by itself and through cooperation with Th1 cytokines (such as IL-12) also regulates Th2 responses (8, 9, 18, 19, 20) to prevent the overproduction of IL-4, IL-5 and IL-13, cytokines that can lead to severe fibrosis in, for example, Schistosoma mansoni (reviewed in Ref. 21), hepatitis C virus (22), and mycobacterial (23) infections. Amelioration of the allergic Th2 responses that can accompany helminth infections also depends on the induction of IL-10 (24). Nevertheless, excessive or mistimed IL-10 production can inhibit the proinflammatory response to Plasmodium spp. (25, 26), Leishmania spp. (27, 28, 29), T. cruzi (30), Mycobacterium spp. (31), and lymphocytic choriomeningitis virus (32, 33) to the extent that pathogens escape immune control, resulting in either fulminant and rapidly fatal or chronic nonhealing infections. For example, during Mycobacterium avium infection very early IL-10 production in BALB/c but not C57BL/6 mice is correlated with the failure of BALB/c mice to control the infection; ablation of IL-10 signaling led to enhanced pathogen control in BALB/c but not C57BL/6 mice, demonstrating the causal relationship between IL-10 and the lack of pathogen control (31). Similarly, in other infections where production of IL-10 correlates with poor pathogen control, experimental ablation of IL-10 or inhibition of IL-10 signaling restores pathogen control and reduces the severity of disease, thereby establishing a direct correlation between inappropriate IL-10 production and disease severity. Conversely, ablation of IL-10 signaling during normally benign infections may augment proinflammatory responses, enhancing pathogen control at the considerable cost of more severe immunopathology (1, 2, 3, 17, 34). However, it is often not clear whether high concentrations of IL-10 during virulent infections are a cause or a consequence of high pathogen burdens. In the former case, IL-10 would directly inhibit pathogen clearance (and may be induced by the pathogen to promote its own survival). Thus, transgenic overexpression of IL-10 (under control of the MHC II promoter) in APC leads to uncontrolled pathogen growth in Leishmania major, Listeria monocytogenes, and M. avium infections (35, 36). In the latter case for example, where the pathogen is able to resist clearance by normally effective mechanisms, IL-10 may be produced to reduce inflammation and thereby minimize pathology. For instance, during virulent infection with the SD strain of L. major, high pathogen loads drive excessive Th1 responses (27) and these, in turn, promote the development of self-limiting adaptive IL-10-producing T cells that dampen down Th1 responses, (28, 37), establishing a positive feedback loop whereby T cell-derived IL-10 further inhibits anti-microbial immune responses, allowing fulminant and inevitably fatal infections to develop. In such cases, IL-10 concentrations often “track” pathogen burdens and systemic IFN-γ concentrations (25, 27, 38).
https://www.jimmunol.org/content/180/9/5771
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