Interleukin-8: An evolving chemokine Matsushima, Kouji; Yang, De; Oppenheim, Joost J.
Cytokine (Philadelphia, Pa.),
20/May , Volume:
153
Journal Article
Peer reviewed
Open access
•IL-8/CXCL8 is the first chemokine discovered.•IL-8 acts on CXCR1/2 to control target cell adhesion, migration, and function.•IL-8 is a crucial regulator of neutrophil trafficking and tumor ...angiogenesis.•Blocking IL-8-CXCR1/2 axis is a key therapeutic target of inflammation and cancer.
Early in the 1980s several laboratories mistakenly reported that partially purified interleukin-1 (IL-1) was chemotactic for neutrophils. However, further investigations by us, revealed that our purified IL-1 did not have neutrophil chemotactic activity and this activity in the LPS-stimulated human monocyte conditioned media could clearly be separated from IL-1 activity on HPLC gel filtration. This motivated Teizo Yoshimura and Kouji Matsushima to purify the monocyte-derived neutrophil chemotactic factor (MDNCF), present in LPS conditioned media and molecularly clone the cDNA for MDNCF. They found that MDNCF protein (later renamed IL-8, and finally termed CXCL8) is first translated as a precursor form consisting of 99 amino acid residues and the signal peptide is then removed, leading to the secretion and processing of biologically active IL-8 of 72 amino acid form (residues 28–99). There are four cysteine residues forming two disulfide linkage and 14 basic amino acid residues which result in a very basic property for the binding of IL-8 to heparan sulfate-proteoglycan. The IL-8 gene consists of 4 exons and 3 introns. IL-8 is produced by various types of cells in inflammation. The 5′-flanking region of IL-8 gene contains several nuclear factor binding sites, and NF-κB in combination with AP-1 or C/EBP synergistically activates IL-8 gene in response to IL-1 and TNFα.
Two receptors exist for IL-8, CXCR1 and CXCR2 in humans, which belong to γ subfamily of GTP binding protein (G-protein) coupled rhodopsin-like 7 transmembrane domain receptors. Rodents express CXCR2 and do not produce IL-8, but produce numerous homologues instead. Once IL-8 binds to the receptor, β and γ subunits of G-protein are released from Gα (Gαi2 in neutrophils) and activate PI3Kγ, PLCβ2/β3, PLA2 and PLD. Gαi2 inhibits adenyl cyclase to decrease cAMP levels. Small GTPases Ras/Rac/Rho/cdc42/Rap1, PKC and AKT (PKB) exist down-stream of β and γ subunits and regulate cell adhesion, actin polymerization, membrane protrusion, and eventually cell migration. PLCβ activation generates IP3 and induces Ca++ mobilization, DAG generation to activate protein kinase C to lead granule exocytosis and respiratory burst.
MDNCF was renamed interleukin 8 (IL-8) at the International Symposium on Novel Neutrophil Chemotactic Activating Polypeptides, London, UK in 1989. The discovery of IL-8 prompted us to also purify and molecularly clone the cDNA of MCAF/MCP-1 responsible for monocyte chemotaxis, and other groups to identify a large family of chemotactic cytokines capable of attracting other types of leukocytes. In 1992, most of the investigators contributing to the discovery of this new family of chemotactic cytokines gathered in Baden, Austria and agreed to name this family “chemokines” and subsequently established the CXCL/CCL and CXCR/CCR nomenclature. The discovery of chemokines resulted in solving the long-time enigma concerning the mechanism of cell type specific leukocyte infiltration into inflamed tissues and provided a molecular basis for immune and hematopoietic cell migration and interactions under physiological as well as pathological conditions.
To our surprise based on its recently identified multifunctional activities, IL-8 has evolved from a neutrophil chemoattractant to a promising therapeutic target for a wide range of inflammatory and neoplastic diseases. IL-8 was initially characterized as a chemoattractant of neutrophils engaged in acute inflammation and then discovered to also be chemotactic for endothelial cells with a major role in angiogenesis. These two activities of IL-8 foster its stimulatory effect on tumor growth. This is abetted by recent additional discoveries showing that IL-8 has stimulatory effects on stem cells and can therefore directly promote the growth of receptor expressing cancer stem cells. IL-8 by interacting with bone marrow stem/progenitor cells has also the capacity to mobilize and release hematopoietic cells into the peripheral circulation. This includes the mobilization of neutrophilic myeloid-derived suppressor cells (N-MDSC) to infiltrate into tumors and thus further promotes the immune escape of tumors. Finally, the capacity of IL-8 to induce trans-differentiation of epithelial cancer cells into mesenchymal phenotype (EMT) increases the malignancy of tumors by promoting their metastatic spread and resistance to chemotherapeutics and cytotoxic immune cells. These observations have stimulated considerable current efforts to develop receptor antagonists for IL-8 and humanized anti-IL-8 antibody for the therapy of cancer, particularly in combination with immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies.
Alarmins and immunity Yang, De; Han, Zhen; Oppenheim, Joost J.
Immunological reviews,
November 2017, Volume:
280, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
More than a decade has passed since the conceptualization of the “alarmin” hypothesis. The alarmin family has been expanding in terms of both number and the concept. It has recently become ...clear that alarmins play important roles as initiators and participants in a diverse range of physiological and pathophysiological processes such as host defense, regulation of gene expression, cellular homeostasis, wound healing, inflammation, allergy, autoimmunity, and oncogenesis. Here, we provide a general view on the participation of alarmins in the induction of innate and adaptive immune responses, as well as their contribution to tumor immunity.
Tumor necrosis factor receptor 2 (TNFR2) is expressed both by some cancer cells and by tumor-infiltrating immunosuppressive CD4
FoxP3
regulatory T cells (T
). TNFR2 stimulates the activation and ...proliferation of T
, a major checkpoint of antitumor immune responses, and promotes cancer cell survival and tumor growth. In this issue of Science Signaling, Torrey et al found that dominant antagonistic antibodies against human TNFR2 may be a potential therapy for ovarian cancer patients by simultaneously suppressing T
activity and inducing the death of the cancer cells.
Review on the reciprocal stimulatory effects of proinflammatory Th17 cells, wth immunosuppressive Treg cells.
Identification of CD4+Foxp3+ Tregs and Th17 modified the historical Th1–Th2 paradigm. ...Currently, the Th17–Tregs dichotomy provides a dominant conceptual framework for the comprehension of immunity/inflammation and tolerance/immunosuppression in an increasing number of diseases. Targeting proinflammatory Th17 cells or immunosuppressive Tregs has been widely considered as a promising therapeutic strategy in the treatment of major human diseases, including autoimmunity and cancer. The efficacy and safety of such therapy rely on a thorough understanding of immunobiology and interaction of these two subsets of Th cells. In this article, we review recent progress concerning complicated interplay of Th17 cells and Tregs. There is compelling evidence that Tregs potently inhibit Th1 and Th2 responses; however, the inhibitory effect of Tregs on Th17 responses is a controversial subject. There is increasing evidence showing that Tregs actually promote the differentiation of Th17 cells in vitro and in vivo and consequently, enhanced the functional consequences of Th17 cells, including the protective effect in host defense, as well as detrimental effect in inflammation and in the support of tumor growth. On the other hand, Th17 cells were also the most potent Th subset in the stimulation and support of expansion and phenotypic stability of Tregs in vivo. These results indicate that these two subsets of Th cells reciprocally stimulate each other. This bidirectional crosstalk is largely dependent on the TNF–TNFR2 pathway. These mutual stimulatory effects should be considered in devising future Th17 cell‐ and Treg‐targeting therapy.
The study of cytokines has evolved from the detection of functional activities present in tissue culture supernatants to the characterization of the three-dimensional molecular structures of the ...cytokines and their receptors. Investigators studying cytokines need to have specialized expertise in using cytokine assays, assessing their receptor interactions, signal transduction, gene activation, and biological effects, and in the therapeutic utilization of agonists and antagonists. Cytokinology can therefore be considered a discipline. In this article, I have considered studies leading to the identification of novel cytokines, potential producers of cytokine mimics such as viruses and the microbiome, and the complex interactions of the cytokine network with our vital functions. Our ever-increasing success in using cytokines and, in particular, cytokine inhibitors therapeutically suggest that cytokinology will eventually become an independent discipline.
High mobility group box‐1 (HMGB1) protein is a nonhistone, DNA‐binding protein that plays a critical role in regulating gene transcription. Recently, HMGB1 has also been shown to act as a late ...mediator of endotoxic shock and to exert a variety of proinflammatory, extracellular activities. Here, we report that HMGB1 simultaneously acts as a chemoattractant and activator of dendritic cells (DCs). HMGB1 induced the migration of monocyte‐derived, immature DCs (Mo‐iDCs) but not mature DCs. The chemotactic effect of HMGB1 on iDCs was pertussis toxin‐inhibitable and also inhibited by antibody against the receptor of advanced glycation end products (RAGE), suggesting that HMGB1 chemoattraction of iDCs is mediated by RAGE in a Gi protein‐dependent manner. In addition, HMGB1 treatment of Mo‐iDCs up‐regulated DC surface markers (CD80, CD83, CD86, and HLA‐A, B,C), enhanced DC production of cytokines (IL‐6, CXCL8, IL‐12p70, and TNF‐α), switched DC chemokine responsiveness from CCL5‐sensitive to CCL21‐sensitive, and acquired the capacity to stimulate allogeneic T cell proliferation. Based on its dual DC‐attracting and ‐activating activities as well as its reported capacity to promote an antigen‐specific immune response, we consider HMGB1 to have the properties of an immune alarmin.
MCP-1/CCL2 plays an important role in the initiation and progression of cancer. Since tumor cells produce MCP-1, they are considered to be the main source of this chemokine. Here, we examined whether ...MCP-1 produced by non-tumor cells affects the growth and lung metastasis of 4T1 breast cancer cells by transplanting them into the mammary pad of WT or MCP-1(-/-) mice. Primary tumors at the injected site grew similarly in both mice; however, lung metastases were markedly reduced in MCP-1(-/-) mice, with significantly longer mouse survival. High levels of MCP-1 mRNA were detected in tumors growing in WT, but not MCP-1(-/-) mice. Serum MCP-1 levels were increased in tumor-bearing WT, but not MCP-1(-/-) mice. Transplantation of MCP-1(-/-) bone marrow cells into WT mice did not alter the incidence of lung metastasis, whereas transplantation of WT bone marrow cells into MCP-1(-/-) mice increased lung metastasis. The primary tumors of MCP-1(-/-) mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of MCP-1, and intravenous injection of 4T1 cells producing a high level of MCP-1 resulted in increased tumor foci in the lung of WT and MCP-1(-/-) mice. Thus, stromal cell-derived MCP-1 in the primary tumors promotes lung metastasis of 4T1 cells, but tumor cell-derived MCP-1 can also contribute once tumor cells enter the circulation. A greater understanding of the source and role of this chemokine may lead to novel strategies for cancer treatment.
Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous ...studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through chemokine receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
Alpha-synuclein (αS) is causally involved in the development of Parkinson disease (PD); however, its role in normal vertebrate physiology has remained unknown. Recent studies demonstrate that αS is ...induced by noroviral infection in the enteric nervous system of children and protects mice against lethal neurotropic viral infection. Additionally, αS is a potent chemotactic activator of phagocytes. In this report, using both wild-type and αS knockout mice, we show that αS is a critical mediator of inflammatory and immune responses. αS is required for the development of a normal inflammatory response to bacterial peptidoglycan introduced into the peritoneal cavity as well as antigen-specific and T cell responses following intraperitoneal immunization. Furthermore, we show that neural cells are the sources of αS required for immune competence. Our report supports the hypothesis that αS accumulates within the nervous system of PD individuals because of an inflammatory/immune response.
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•Peritoneal inflammation triggers αS production by neurons that innervate peritoneum•αS activates APCs by triggering TLR4 and promotes innate and adaptive immune responses•Neuronal αS is required for the induction of peritonitis and immune responses•αS-triggered immune responses may contribute to PD development and/or progression
Alam et al. show that αS produced by the neurons of the gastrointestinal system is critical for the manifestation of peritoneal inflammation and systemic antigen-specific immune responses, which may in turn, promote neuronal αS accumulation and contribute to the development and/or progression of Parkinson disease.
The recruitment and activation of antigen-presenting cells are critical early steps in mounting an immune response. Many microbial components and endogenous mediators participate in this process. ...Recent studies have identified a group of structurally diverse multifunctional host proteins that are rapidly released following pathogen challenge and/or cell death and, most importantly, are able to both recruit and activate antigen-presenting cells. These potent immunostimulants, including defensins, cathelicidin, eosinophil-derived neurotoxin, and high-mobility group box protein 1, serve as early warning signals to activate innate and adaptive immune systems. We propose to highlight these proteins’ unique activities by grouping them under the novel term ‘alarmins’, in recognition of their role in mobilizing the immune system.
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