• Animal cells and systems
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• v.2 no.2
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• pp.153-164
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• 1998

Cytokines regulate proliferation, differentiation and functions of haemotopoietic cells. Each cytokine possesses a variety of activities on various target cells (pleiotropy) and various cytokines have similar and overlapping activities on the same target cells (redundancy). The nature of these cytokine activities predicts unique feature of cytokine receptors, namely, cytokine has multiple receptors, different cytokines share a common receptor, and different cytokine receptors are linked to common signaling pathways. cDNA cloning of genes for cytokine receptors revealed distinct sets of receptor family with different structural features. The cytokine receptor superfamily consists of a largest family, and contains more than twenty cytokine receptor subunits. This receptor has common structural features in both extracellular and intracellular regions without tyrosine kinase domain. Another striking feature of the receptor is to share common subunit of multiple cytokines, which partly explains the redundancy of activities of some cytokines. Recent studies revealed detailed signaling events of the cytokine receptor, the primary activation of JAK and subsequent phosphorylation of tyrosine residues of receptor, and various cellular proteins. Many SH2 containing adapter proteins play an important role in cytokine signals, and this system has similarities with tyrosine kinase receptor signal transduction. STAT may mainly account for cytokine specific functions as suggested by knockout mice studies. It is of importance to note that cytokine activates multiple signaling pathways and the balance and combination of related signaling events may determine the specificity of functions of cytokines.

• Parasites, Hosts and Diseases
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• v.59 no.6
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• pp.547-556
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• 2021

Our objective was to investigate whether inflammatory microenvironment induced by Trichomonas vaginalis infection can stimulate proliferation of prostate cancer (PCa) cells in vitro and in vivo mouse experiments. The production of CXCL1 and CCL2 increased when cells of the mouse PCa cells (TRAMP-C2 cell line) were infected with live T. vaginalis. T. vaginalis-conditioned medium (TCM) prepared from co-culture of PCa cells and T. vaginalis increased PCa cells migration, proliferation and invasion. The cytokine receptors (CXCR2, CCR2, gp130) were expressed higher on the PCa cells treated with TCM. Pretreatment of PCa cells with antibodies to these cytokine receptors significantly reduced the proliferation, mobility and invasiveness of PCa cells, indicating that TCM has its effect through cytokine-cytokine receptor signaling. In C57BL/6 mice, the prostates injected with T. vaginalis mixed PCa cells were larger than those injected with PCa cells alone after 4 weeks. Expression of epithelial-mesenchymal transition markers and cyclin D1 in the prostate tissue injected with T. vaginalis mixed PCa cells increased than those of PCa cells alone. Collectively, it was suggested that inflammatory reactions by T. vaginalis-stimulated PCa cells increase the proliferation and invasion of PCa cells through cytokine-cytokine receptor signaling pathways.

• IMMUNE NETWORK
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• v.10 no.1
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• pp.26-34
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• 2010

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease that develops following repeated exposure to inhaled particulate antigens. The family of $Fc{\gamma}$ receptors ($Fc{\gamma}Rs$) has emerged as central regulators for modulating both pro-and anti-inflammatory responses. However, the role of $Fc{\gamma}Rs$ in the development of HP has not been investigated yet. Methods: To explore the functional roles of $Fc{\gamma}Rs$ in HP, $Fc{\gamma}R^{-/-}$ and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally, and compared these mice in terms of the histological change, infiltrated immune cells in BALF and in vitro immune responses. Results: $Fc{\gamma}R^{-/-}$ mice exhibited attenuation of HP in terms of histological alterations, and reduced numbers of neutrophils and macrophages in and the increased CD4 : CD8 ratio of bronchoalveolar lavage fluid. The lungs of $Fc{\gamma}R^{-/-}$ mice showed high production of Th2 cytokine such as IL-4 and slightly low production of Th1 cytokine, INF-${\gamma}$ compared to those of B6 mice. However, SR-specific adaptive immune responses of $Fc{\gamma}R^{-/-}$ mice were similar to those of B6 mice. Conclusion: These results demonstrate that activating $Fc{\gamma}$ receptors play an important role in activating neutrophils and macrophages in pulmonary inflammation and inducing Th1 differentiation by regulating cytokine expression in SR-induced HP.

• Parasites, Hosts and Diseases
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• v.59 no.6
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• pp.557-564
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• 2021

Macrophages play a key role in chronic inflammation, and are the most abundant immune cells in the tumor microenvironment. We investigated whether an interaction between inflamed prostate cancer cells stimulated with Trichomonas vaginalis and macrophages stimulates the proliferation of the cancer cells. Conditioned medium was prepared from T. vaginalis-infected (TCM) and uninfected (CM) mouse prostate cancer (PCa) cell line (TRAMP-C2 cells). Thereafter conditioned medium was prepared from macrophages (J774A.1 cell line) after incubation with CM (MCM) or TCM (MTCM). When TRAMP-C2 cells were stimulated with T. vaginalis, protein and mRNA levels of CXCL1 and CCL2 increased, and migration of macrophages toward TCM was more extensive than towards CM. Macrophages stimulated with TCM produced higher levels of CCL2, IL-6, TNF-α, their mRNAs than macrophages stimulated with CM. MTCM stimulated the proliferation and invasiveness of TRAMP-C2 cells as well as the expression of cytokine receptors (CCR2, GP130, CXCR2). Importantly, blocking of each cytokine receptors with anti-cytokine receptor antibody significantly reduced the proliferation and invasiveness of TRAMP-C2 cells. We conclude that inflammatory mediators released by TRAMP-C2 cells in response to infection by T. vaginalis stimulate the migration and activation of macrophages and the activated macrophages stimulate the proliferation and invasiveness of the TRAMP-C2 cells via cytokine-cytokine receptor binding. Our results therefore suggested that macrophages contribute to the exacerbation of PCa due to inflammation of prostate cancer cells reacted with T. vaginalis.

• IMMUNE NETWORK
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• v.11 no.6
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• pp.424-427
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• 2011

The nucleotide-oligomerization domain (NOD) proteins are members of the NOD-like receptor (NLR) family, which are intracellular and cytoplasmic receptors. We analyzed the role of NODs for cytokine production by macrophages infected with intracellular pathogen M. leprae, the causative agent of leprosy. Production of pro-inflammatory cytokines such as IL-$1{\beta}$ and TNF-${\alpha}$ was inhibited in the presence of cytochalasin D, an agent blocking phagocytosis, suggesting that intracellular signaling was, partially, required for macrophage activation to M. leprae infection. Next, we investigated the role of NOD1 and NOD2 proteins on NF-${\kappa}B$ activation and cytokine expression. Treatment with M. leprae significantly increased NF-${\kappa}B$ activation and expression of TNF-${\alpha}$ and IL-$1{\beta}$ in NOD1- and NOD2-transfected cells. Interestingly, their activation and expression were inhibited by cytochalasin D, suggesting that stimulation of NOD proteins may be associated with the enhancement of cytokine production in host to M. leprae.

• BMB Reports
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• v.43 no.2
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• pp.91-96
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• 2010

The function of macrophage inhibitory cytokine-1 (MIC-1) in cancer remains controversial, and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of EGFR, ErbB2, and ErbB3 through the activation of c-Src in SK-BR-3 breast cells. MIC-1 induced significant phosphorylation of EGFR at Tyr845, ErbB2 at Tyr877, and ErbB3 at Tyr1289 as well as Akt and p38, Erk1/2, and JNK mitogen-activated protein kinases (MAPKs). Treatment of SK-BR-3 cells with MIC-1 increased the phosphorylation level of Src at Tyr416, and induced invasiveness of those cells. Inhibition of c-Src activity resulted in the complete abolition of MIC-1-induced phosphorylation of the EGFR, ErbB2, and ErbB3, as well as invasiveness and matrix metalloproteinase (MMP)-9 expression in SK-BR-3 cells. Collectively, these results show that MIC-1 may participate in the malignant progression of certain cancer cells through the activation of c-Src, which in turn may transactivate ErbB-family receptors.

• IMMUNE NETWORK
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• v.10 no.4
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• pp.120-125
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• 2010

Dysfunction of the virus-specific T cells is a cardinal feature in chronic persistent viral infections such as one caused by hepatitis C virus (HCV). In chronic HCV infection, virus-specific dysfunctional CD8 T cells often overexpress various inhibitory receptors. Programmed cell death 1 (PD-1) was the first among these inhibitory receptors that were identified to be overexpressed in functionally impaired T cells. The roles of other inhibitory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) have also been demonstrated in T-cell dysfunctions that occur in chronic HCV patients. Blocking these inhibitory receptors in vitro restores the functions of HCV-specific CD8 T cells and allows enhanced proliferation, cytolytic activity and cytokine production. Therefore, the blockade of the inhibitory receptors is considered as a novel strategy for the treatment of chronic HCV infection.

• The Journal of Internal Korean Medicine
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• v.30 no.1
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• pp.9-23
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• 2009

Objectives : Asthma is a chronic inflammatory disorder of the airways by many cells such as mast cells, Th2 lymphocytes and eosinophile. The present study was aimed to evaluate the effects of Salviae miltiorrhizae (SM) on T cell cytokine production, mast cells. and eosinophils, Methods : We screened 13 herbs to find compounds with potential to control Th cytokine production. using concanavalin A (con A)-activated splenocyte cultures. Con A-activated $IFN-\gamma$ and IL-4 levels in supernatants of splenocyte cultures. Bone marrow derived mast cells (BMMC) were incubated with SM and then the expressions of membrane proteins of BMMC were analyzed by fluorescence activated cell sorter (FACS). BALB/c mice sensitized to ovalbumin (OVA) were challenged with aerosolized OVA for 6 weeks. During the last weeks some mice were treated with SM. Then eosinophils in bronchoalveolar lavage fluid (BALf) were counted and pathologic changes of lung tissue were observed with hematoxylin-eosin stain. Results : SM increased $IFN-\gamma$ level on splenocyte culture significantly. but had no significant effects on expressions of ICAM-1, CD62L, integrin $a_4$. c-kit, IL-3 receptors. CD11a, or IgE receptors of BMMC. SM treatment significantly inhibited eosinophil infiltrates in BALf and peribronchial lung inflammation. Conculusions : The present data suggested that SM may have an effect on Th cytokine secretion and eosinophils associated with asthma responses. Therefore SM might be of therapeutic value in treating asthma.

• The Korean Journal of Pain
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• v.22 no.1
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• pp.1-15
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• 2009

Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.

• Molecules and Cells
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• v.42 no.1
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• pp.1-7
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• 2019

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.