Keita Kasahara

Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung.

A number of novel chemotactic cytokines are becoming increasingly recognized as important participants in the elicitation of specific inflammatory cells from the peripheral blood to sites of inflammation. Recent observations have now demonstrated that certain chemotactic cytokines possess specificity for the selected movement of individual immune/inflammatory cell populations. One of the more studied chemotactic cytokines is a neutrophil chemotactic factor identified as interleukin-8 (IL-8). This polypeptide mediator is produced in abundance by mononuclear phagocytic cells, as well as a number of non-inflammatory cells. This latter list includes both fibroblasts and epithelial cells. Moreover, the synthesis of IL-8 by fibroblasts and epithelial cells involves stimulus specificity, as the production of this mediator by non-inflammatory cells is dependent upon an initial host response. In the context of the lung, the alveolar macrophage appears to play a central role by generating factors, such as interleukin-1 and tumor-necrosis factor, which are potent stimuli for the induction of IL-8 by the lung fibroblasts and type II epithelial cells. The cascade-like interaction may lead to the rapid production of significant quantities of IL-8 by the lung and may selectively recruit neutrophils to the pulmonary interstitium and/or airspace. This sequence of events, which leads to cytokine networking in the lung, may be an important phenomenon for the generation of a major chemotaxin important to a variety of lung diseases.

Human neutrophils exhibit disparate chemotactic factor gene expression

The evolution of acute inflammation from initiation through resolution is associated with the changing character of the infiltrating leukocytes. Recruitment of these leukocytes is dependent upon the generation of chemotactic factors that have either global or specific activity for a particular leukocyte. In this manuscript we present data demonstrating that human neutrophils can express mRNA for neutrophil chemotactic factor/interleukin 8 (IL-8), but fail to express mRNA for monocyte chemotactic protein (MCP-1). The expression of IL-8 was observed upon adherence or in response to stimulation with lipopolysaccharide. Maximal IL-8 antigenic production was noted at 24 hrs. These studies demonstrate a disparate expression of chemotactic cytokines by neutrophils.

Mononuclear cell adherence induces neutrophil chemotactic factor/interleukin-8 gene expression.

The accumulation of polymorphonuclear cells (PMN) in tissue is an essential element of the inflammatory response that is important in host defense. Adherence to endothelium constitutes the first step in PMN migration from the vascular compartment to the interstitium. We demonstrate that human peripheral blood mononuclear cells (PBMC) adherent to plastic can result in expression of interleukin‐8 (IL‐8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed IL‐8 steady‐state mRNA levels by 30 min, peaked at 8 h, and then decreased over the next 16 h. In contrast, nonadherent PBMC (cultured in teflon chambers) expressed less than 25% of the maximal IL‐8 steady‐state mRNA levels as compared with adherent PBMC. Adherent PBMC‐associated IL‐8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic IL‐8 paralleled IL‐8 mRNA expression. Antigenic and bioactive IL‐8 were significantly apparent by 4–8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC IL‐8 gene expression was suppressed by either concomitant treatment with actinomycin‐D or cycloheximide, yet specific neutralizing antibodies directed against either IL‐1β or tumor necrosis factor (TNF)‐α failed to alter adherence‐induced steady‐state IL‐8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of IL‐8, and may be essential to the development of the inflammatory response through the elicrtation of PMN.

Disparate regulation of interleukin 8 gene expression from blood monocytes, endothelial cells, and fibroblasts by interleukin 4

The role(s) of novel chemotactic cytokines as mediators in the pathogenesis of many acute and chronic disease states is becoming increasingly apparent. One of these cytokines, interleukin 8, is a product of both immune and non-immune cells. In this manuscript, we describe the suppression of IL-8 gene expression from stimulated monocytes by IL-4, while IL-4 had no suppressive effects on IL-8 gene expression from stimulated fibroblasts and endothelial cells. Our data suggest that IL-4 may function as an endogenous regulator of monocyte cytokine expression, including the chemotactic cytokine IL-8.

Adherence in combination with lipopolysaccharide, tumor necrosis factor or interleukin-1β potentiates the induction of monocyte-derived interleukin-8

In this study we demonstrate that adherence of peripheral blood mononuclear cells (PBMC) to either plastic or extracellular matrix, such as collagen type I or fibronectin, is a significant stimulus for the induction of both interleukin-8 (IL-8) mRNA and antigen. In addition, adherence of PBMC in the presence of lipopolysaccharide, interleukin-1-beta, or tumor necrosis factor-alpha greatly enhances transcription/translation of IL-8 from these leukocytes. Our findings demonstrate that PBMC adherent to either plastic or physiological surfaces in combination with an inflammatory agonist is both a potent and efficacious signal for the expression and production of the neutrophil chemotactic/activating cytokine, IL-8.

Stimulus Specific Induction of Monocyte Chemotactic Protein-1 (MCP-1) Gene Expression

The recruitment of monocytes from the peripheral vasculature to an area of chronic inflammation is a complex phenomenon. This complicated process is likely mediated to a large extent by chemotactic cytokines that are expressed via a cytokine cascade. A number of chronic diseases that are difficult to manage are characterized by a significant infiltrate of monocytes, including sarcoidosis, Wegeners granulomatosis, and tuberculosis. New scientific insight into the mechanisms that lead to early activation events, such as monocyte elicitation, may aid in both better understanding these diverse processes and designing more effective therapies.

Induction and Regulation of Interleukin-8 Gene Expression

Recent advances in understanding granulocyte elicitation have been made with the discovery and isolation of chemotactic cytokines. There is little doubt that these polypeptides will prove to be important mediators of disease process. Therefore, studies directed at understanding the production and regulation of interleukin-8 will continue to be a fertile area to explore mechanisms of disease processes and therapeutic targets.