IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulates hematopoiesis and causes neutrophilia consisting of mature granulocytes. In this study, we show that IL-17-mediated granulopoiesis requires G-CSF release and the presence or induction of the transmembrane form of stem cell factor (SCF) for optimal granulopoiesis. However, IL-17 also protects mice from G-CSF neutralization-induced neutropenia. G-CSF neutralization completely reversed IL-17-induced BM progenitor expansion, whereas splenic CFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sld and littermate control mice. Thus, there remained a significant SCF/G-CSF-independent effect of IL-17 on splenic granulopoiesis, resulting in a preservation of mature circulating granulocytes. IL-17 is a cytokine that potentially interconnects lymphocytic and myeloid host defense and may have potential for therapeutic development.

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Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis.

Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese.

Innate immune cells, particularly macrophages and epithelial cells, play a key role in multiple layers of immune responses. Alarmins and pro-inflammatory cytokines from the IL (interleukin)-1 and TNF (tumour necrosis factor) families initiate the cascade of events by inducing chemokine release from bystander cells and by the up-regulation of adhesion molecules required for transendothelial trafficking of immune cells. Furthermore, innate cytokines produced by dendritic cells, macrophages, epithelial cells and innate lymphoid cells seem to play a critical role in polarization of helper T-cell cytokine profiles into specific subsets of Th1/Th2/Th17 effector cells or regulatory T-cells. Lastly, the innate immune system down-regulates effector mechanisms and restores homoeostasis in injured tissue via cytokines from the IL-10 and TGF (transforming growth factor) families mainly released from macrophages, preferentially the M2 subset, which have a capacity to induce regulatory T-cells, inhibit the production of pro-inflammatory cytokines and induce healing of the tissue by regulating extracellular matrix protein deposition and angiogenesis. Cytokines produced by innate immune cells represent an attractive target for therapeutic intervention, and multiple molecules are currently being tested clinically in patients with inflammatory bowel disease, rheumatoid arthritis, systemic diseases, autoinflammatory syndromes, fibrosing processes or malignancies. In addition to the already widely used blockers of TNFα and the tested inhibitors of IL-1 and IL-6, multiple therapeutic molecules are currently in clinical trials targeting TNF-related molecules [APRIL (a proliferation-inducing ligand) and BAFF (B-cell-activating factor belonging to the TNF family)], chemokine receptors, IL-17, TGFβ and other cytokines.

Cytokine networking of innate immunity cells: a potential target of therapy.

Eosinophils are evolutionarily conserved, pleotropic cells that display key effector functions in allergic diseases, such as asthma. Nonetheless, eosinophils infiltrate multiple tumours and are equipped to regulate tumour progression either directly by interacting with tumour cells or indirectly by shaping the tumour microenvironment (TME). Eosinophils can readily respond to diverse stimuli and are capable of synthesizing and secreting a large range of molecules, including unique granule proteins that can potentially kill tumour cells. Alternatively, they can secrete pro-angiogenic and matrix-remodelling soluble mediators that could promote tumour growth. Herein, we aim to comprehensively outline basic eosinophil biology that is directly related to their activity in the TME. We discuss the mechanisms of eosinophil homing to the TME and examine their diverse pro-tumorigenic and antitumorigenic functions. Finally, we present emerging data regarding eosinophils as predictive biomarkers and effector cells in immunotherapy, especially in response to immune checkpoint blockade therapy, and highlight outstanding questions for future basic and clinical cancer research.

A new dawn for eosinophils in the tumour microenvironment.

CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4.

Interleukin 3 (IL-3) induces proliferation and differentiation of mast cell progenitors in vitro, whereas it induces granulocytosis in vivo. In this paper, a positive feedback mechanism of granulopoiesis was studied in order to elucidate the granulocytosis induced by IL-3 in mouse. IL-3 induced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in total bone marrow cells and a marrow adherent cell population. In fractionated marrow cell populations, a different expression pattern of induction by IL-3 stimulation was observed; GM-CSF was expressed in macrophages and fraction 1 (P<1.061) and 2(1.061<P<1.074) of bone marrow cells fractionated by equilibrium density centrifugation, G-CSF was expressed in macrophages and fraction 2 and 3 (1.074<P<1.097), and interleukin 6 (IL-6) in macrophages and fraction 1 to 3. These results indicate a hierarchical regulation of cytokine production and the existence of a positive feedback mechani...

Induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in bone marrow and fractionated marrow cell populations by interleukin 3 (IL-3): IL-3-mediated positive feedback mechanisms of granulopoiesis.

We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/gtc.12371

CCL11‐induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis

Some members of the integrin family recognize the RGD sequence which is common to cell adhesive proteins in a divalent cation-dependent manner. In the presence of Ca2+ and Mg2+, the fibronectin receptor of placenta recognizes the RGD sequence of fibronectin, but not that of vitronectin, while the vitronectin receptor of placenta recognizes the RGD sequence of vitronectin, but not that of fibronectin, although both receptors recognize the same RGD sequence. We have found by performing an enzyme-linked immunosorbent assay (ELISA) using receptor-specific monoclonal antibodies and by electrophoretic analysis that in the presence of Mn2+ a vitronectin receptor of placenta binds to an affinity column coupled with the cell-binding domain of fibronectin. By replacing divalent cations from Mn2+ to Ca2+ and Mg2+, the vitronectin receptor was completely eluted from the column. When the synthetic peptides GRGDSP and GRGESP were applied to the column as competitors, the Mn(2+)-dependent binding was inhibited by both peptides. These results suggest that Mn2+ elicits a binding activity of the placenta vitronectin receptor to the RGD site of fibronectin. The modulation of ligand specificity by Mn2+ will provide an important clue in the elucidation of the cause of individual ligand specificity of RGD-recognizing integrins.

Manganese ion elicits a binding activity of placenta vitronectin receptor to fibronectin cell-binding domain.

Hemopoietic stem cells adhere to hemopoietic supportive (MS-5) cells, but not to non-supportive (MS-K) cells. Although a soluble stem cell factor (SCF) was produced by both of these cell lines, little activity was detectable in the supernatant from the cultures of either of these cells, indicating that SCF might be compartmentalized within the extracellular matrix (ECM), and transferred directly to the stem cells via the ECM (44). To probe this possibility, we studied the transfer of SCF from the ECM and the subsequent support of the survival of the hemopoietic stem cells. A stem cell-enriched bone marrow cell fraction was overlaid on SCF-containing ECM. The stem cells survived and proliferated for some days without differentiation under these conditions, whereas stem cells overlaid on ECM without SCF died within a few days. Addition of interleukin-3 (IL-3) to the ECM that contains SCF, induced differentiation of the stem cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced further differentiation of the stem cells, which was accompanied by a decrease in the number of colony-forming unit in spleen (CFU-S). These observations verified the above hypothesis, and indicated that the survival, the self-renewal, and the differentiation of hemopoietic stem cells can be separately controlled at least in vitro.

Separate Control of the Survival, the Self-renewal and the Differentiation of Hemopoietic Stem Cells

http://www.cdb.riken.jp/org/pdf/monograph/pub-1994-2.pdf

Takanori Yanai

Papers

Induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in bone marrow and fractionated marrow cell populations by interleukin 3 (IL-3): IL-3-mediated positive feedback mechanisms of granulopoiesis.

CCL11‐induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis

Manganese ion elicits a binding activity of placenta vitronectin receptor to fibronectin cell-binding domain.

Separate Control of the Survival, the Self-renewal and the Differentiation of Hemopoietic Stem Cells

Constitutive production of IL-6 in the anemic mice of W/Wv genotype.