Abstract
Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 β, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.
In the bone marrow, monocytes differentiate from multipotent myeloid stem cells. They are released into the peripheral circulation, where they circulate for several days. Thereafter they migrate into various tissues and become macrophages. During differentiation of monocytes to macrophages, they are educated by the tissue environment and acquire tissue-specific functions (1, 2). It is believed that macrophages play important roles in the maintenance of homeostasis, host defense mechanisms (such as phagocytosis of cancer cells), and tissue remodeling (3, 4). Reportedly, macrophages accumulate in tumor tissues and adipose tissues of obesity (5, 6). Moreover, it has been demonstrated that macrophages that accumulate in tumor tissues or adipose tissues of obesity differentiate by interacting with cancer cells or adipocytes, thereby inducing inflammatory changes in the tissues by increasing the expression of inflammatory cytokines (7, 8). Inflammatory changes in the tissues are believed to cause chronic inflammation; chronic inflammation has been demonstrated to be involved in the development of cancer, lifestyle-related diseases included in the metabolic syndrome such as diabetes, stroke, and arteriosclerosis diseases, and autoimmune diseases (9, 10). It also influences the severity of these diseases. The macrophage phenotype is therefore important in mediating inflammatory changes in tissues.
Lipopolysaccharide (LPS), an extracellular membrane component of gram-negative bacteria, is known to induce the expression of inflammatory cytokines through toll-like receptor-4 (11). When LPS is intravenously administered at a high concentration, inflammatory cytokines are systemically produced from activated macrophages, causing acute septic shock (12). Recent research has demonstrated differences between the effects of macrophages activated with low-dose LPS and those activated with high-dose LPS, suggesting LPS acts more as an exohormone than as an endotoxin (13). Additionally, LPS has been demonstrated to be non-toxic, when administered orally and dermally (14). Environmental exposure to LPS in childhood has been suggested to play an important role in the development of tolerance to ubiquitous allergens, and LPS signal transduction was essential for skin wound healing (15, 16). However, the significance of low-dose LPS has not been fully elucidated. Further investigation in this area may lead to development of novel approaches to prevent cancer and lifestyle-related diseases.
Monocytes/Macrophages Activated with Low-dose LPS Suppress Macrophage Migration into Tissues
In monocyte chemotactic protein (MCP)-1-deficient and MCP-1 receptor, C-C chemokine receptor (CCR)-2-deficient mice, the number of macrophages in adipose tissue of obesity induced by a high fat diet was significantly reduced compared to those in wild type mice (17-19). Alternatively, in transgenic mice overexpressing MCP-1, the number of macrophages to adipose tissue of obesity induced by a high fat diet was significantly increased compared to those in wild type mice (20). The migration of macrophages into adipose tissues was demonstrated to be performed via the MCP-1 receptor, CCR-2. MCP-1 is therefore considered to be an important molecule contributing to macrophage migration into adipose tissues. Furthermore, MCP-1 is shown to be involved in the migration of monocytes to the vessel wall at the beginning of arteriosclerosis (21).
Monocytes activated with low-dose LPS (100 pg/ml) were co-cultured with cancer cells or adipocytes using a transwell system. The results revealed that increased expression of MCP-1 was suppressed not only in monocytes but also in cancer cells and adipocytes (22, 23). Furthermore, the expression of MCP-1 was significantly reduced in mouse macrophages after low-dose LPS pre-treatment compared with that after high-dose LPS pre-treatment (24). These results suggest that monocytes/macrophages activated with low-dose LPS suppress increased expression of MCP-1. It is therefore possible that monocytes/macrophages activated with low-dose LPS have a suppressive effect on migration into tissues and the intima of arteriosclerosis.
Monocytes/Macrophages Activated with Low-dose LPS Suppress Inflammatory Changes in Tissues
Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase the expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues, and possibly causing chronic inflammation. The increased expression of inflammatory cytokines (interleukin (IL)-1 β, IL-8, and tumor necrosis factor (TNF)-α) in human monocytes by co-culture with human cancer cells or adipocytes using a transwell system was reportedly suppressed by pre-treatment with low-dose LPS (100 pg/ml) (22, 23). In addition, the increased expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-β) in human monocytes by co-culture with human cancer cells using a transwell system was suppressed by pre-treatment with low-dose LPS (25, 26). Furthermore, mouse macrophages activated with low-dose LPS (50 pg/ml) were shown to suppress the increased expression of IL-6 (27). The induction of MCP-1 suggests to play a role in the early stage of inflammatory changes in tissues (7). MCP-1 is also considered as a key molecule contributing to the inflammatory changes in adipose tissues. In MCP-1-deficient and CCR-2-deficient mice, the expression of TNF-α significantly decreased and that of adiponectin significantly increased in the adipose tissue compared to those in wild type mice, while systemic insulin resistance improved (18, 19). In transgenic mice overexpressing MCP-1, the expression of TNF-α significantly increased in the adipose tissue compared to those in wild type mice, while systemic insulin resistance deteriorated (20). It is therefore possible that monocytes/macrophages activated with low-dose LPS regulate chronic inflammation in tissues by suppressing inflammatory changes.
Moreover, the increased expression of an angiogenesis-related factor, vascular endothelial growth factor-A in human monocytes by co-culture with human cancer cells using a transwell system was suppressed by pre-treatment with low-dose LPS (100 pg/ml) (22). Therefore, monocytes/macrophages activated with low-dose LPS may suppress the invasion and metastasis of cancer by suppressing angiogenesis.
Monocytes/Macrophages Activated with Low-dose LPS Regulate the Expression of Immune Response-related Factors
Macrophages respond to LPS signaling via nuclear factor (NF)-ĸB (3), and upon activation with high-dose LPS, enhance the production of this transcription factor. Mouse macrophages activated with low-dose LPS reportedly exhibited reduced expression of RelB, a member of the NF-ĸB transcription factor family, and failed to activate the classical NF-ĸB pathway (24). By both activating and repressing immune response-related factors, RelB is believed to function as a dual transcriptional regulator during LPS tolerance and severe systemic inflammation, respectively (28). The increased expression of RelB in human monocytes by co-culture with human cancer cells using a transwell system was suppressed by pre-treatment with low-dose LPS (100 pg/ml) (25). Monocytes/macrophages activated with low-dose LPS may be attributed to regulating the expression of RelB.
Moreover low-dose LPS was shown opposite effects on IL-1 receptor-associated kinase 1 (IRAK1) and PI3K pathways as compared to high-dose LPS, leading to an opposing regulation of RelB in IRAK1-deficient mice (29). Monocytes/macrophages activated with low-dose LPS thus appear to regulate the expression of immune response-related factors. It is possible that monocytes/macrophages activated with low-dose LPS restore the original function, such as the maintenance of homeostasis.
Conclusion
Monocytes/macrophages play an important role in the immune system. Educated by the tissue microenvironment, they terminally differentiate into various types of macrophages with tissue-specific characteristics. Monocytes/macrophages activated with low-dose LPS may regulate inflammatory changes in tissues by inducing different functions of macrophages. The effects of monocytes/macrophages activated with low-dose LPS were different from those of monocytes/macrophages activated with high-dose LPS. Moreover, monocytes/macrophages activated with low-dose LPS have been reported to regulate the expression of RelB, which functions as a dual transcriptional regulator during an immune response (28). Low-dose LPS treatment may, therefore, be useful in developing therapies for cancer, lifestyle-related diseases, and autoimmune diseases, by preventing chronic inflammation.
Footnotes
Authors' Contributions
All Authors have contributed to data collection and interpretation. TH drafted the manuscript, HI contributed to reviewing and editing the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest for this article.
- Received May 23, 2019.
- Revision received June 23, 2019.
- Accepted June 24, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
References
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- Monocytes/Macrophages Activated with Low-dose LPS Suppress Macrophage Migration into Tissues
- Monocytes/Macrophages Activated with Low-dose LPS Suppress Inflammatory Changes in Tissues
- Monocytes/Macrophages Activated with Low-dose LPS Regulate the Expression of Immune Response-related Factors
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