Synergy in cytokine and chemokine networks amplifies the inflammatory response

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Abstract

The inflammatory response is a highly co-ordinated process involving multiple factors acting in a complex network as stimulators or inhibitors. Upon infection, the sequential release of exogenous agents (e.g. bacterial and viral products) and induction of endogenous mediators (e.g. cytokines and chemokines) contribute to the recruitment of circulating leukocytes to the inflamed tissue. Microbial products trigger multiple cell types to release cytokines, which in turn are potent inducers of chemokines. Primary cytokines act as endogenous activators of the immune response, whereas inducible chemokines act as secondary mediators to attract leukocytes. Interaction between exogenous and endogenous mediators thus enhances the inflammatory response. In this review, the synergistic interaction between cytokines to induce chemokine production and the molecular mechanisms of the cooperation amongst co-induced chemokines to further increase leukocyte recruitment to the site of inflammation are discussed.

Introduction

The release of exogenous agents (e.g. bacterial and viral products) and the subsequent induction of endogenous mediators (e.g. cytokines and chemokines) during the inflammatory response, contribute to the recruitment of circulating leukocytes. These become activated at the site of infection and release secondary messengers capable of microbe killing (e.g. oxygen radicals) and tissue remodeling (e.g. proteases) [1], [2], [3], [4]. Among the host-derived products, cytokines play a key role in the attraction of leukocytes as potent inducers of chemokines. Therefore, cytokines, such as interleukin-1 (IL-1) and interferons (IFN), which are induced by viral (e.g. double stranded RNA) or bacterial (e.g. endotoxins) products act as primary activators of the immune response, whereas chemokines rather act as secondary mediators capable of attracting inflammatory cells. In response to infection, cytokines and chemokines are produced simultaneously and may interact in a complex network as either stimulators or inhibitors of inflammation.

In addition to a variety of tissue cells, that can secrete cytokines, two principal types of immune cells, i.e. the T helper (TH) cell and the macrophage are potent producers of cytokines. T lymphocytes undergo complicated patterns of differentiation from uncommitted precursors to highly competent effector cells of at least two distinct T helper subsets, TH1 and TH2. These are defined by their function and their distinct cytokine production profile. Activated CD4+ TH cells exert most of their helper functions through secretion of cytokines. The two CD4+ TH cell subpopulations, designated TH1 and TH2, can also be distinguished by the cytokines they secrete in vitro. The TH1 subset is responsible for many cell-mediated functions (e.g. activation of macrophages and the killing of intracellular parasites) and mainly secrete IFN-γ, tumor necrosis factor-β (TNF-β) and IL-2, whereas the TH2 subset participates primarily in humoral and allergic responses (e.g. production of antibodies, in particular IgE and an associated eosinophilia) by producing IL-4, IL-5 and IL-13. In contrast, the major proinflammatory cytokines IL-1β and TNF-α, which share many biological activities, are mainly produced by macrophages [5].

Cytokines act on cells by inducing the increased expression of several genes. The spectrum of the cytokine-induced genes varies depending on the cell type and on the interaction with other cytokines. In some cases, there is a synergistic interaction between (pro)inflammatory cytokines to induce the release of chemokines by a specific cell type.

Section snippets

Synergistic induction of chemokines by cytokines and microbial agents

Microbial infection is characterized by the upregulation of multiple cytokine genes. For example, viral double stranded RNA (dsRNA) is a potent inducer of interferon, hematopoietic colony stimulating factors and chemokines in tissue fibroblasts [6], [7], [8], [9], whereas bacterial endotoxins induce interleukins IL-1, TNF-α and chemokines in monocytes [10], [11], [12]. Although by itself not chemotactic in vitro, both LPS and IL-1 were found to provoke granulocyte infiltration upon intradermal

Chemokine-cytokine interactions

As mentioned before, cytokines synergize to induce the production of chemokines, which may, in turn, cooperate to chemoattract leukocytes. Now, what about the potential interaction between chemokines and cytokines, which are secreted simultaneously during an inflammatory response?

For example, massive infiltration of eosinophils is a feature of allergic diseases. The fact that only small numbers of circulating or resident eosinophils are observed under physiological conditions, suggests the

Concluding remarks

Upon infection, the sequential release of exogenous agents (e.g. bacterial and viral products) and induction of endogenous mediators (e.g. cytokines and chemokines) contributes to the recruitment of circulating leukocytes to the inflamed tissue. There exist many different ways to enhance or reduce the inflammatory response. Cytokines are fundamental regulators of chemokine production in different cell types and their antagonism or synergism may dictate the type of cellular infiltrate and the

Acknowledgements

Financial support: This work was supported by the Fund for Scientific Research of Flanders (F.W.O.-Vlaanderen), the Concerted Research Actions (G.O.A.) of the Regional Government of Flanders, the InterUniversity Attraction Poles Programme-Belgian Science Policy (I.U.A.P.), the European Union 6FP, EC contract INNOCHEM. P.P. and S.S. are senior research assistants of the F.W.O.-Vlaanderen. The authors thank Prof. J. Ceuppens (K.U.Leuven, Belgium), Prof. P. Matthys (K.U.Leuven, Belgium), Prof. G.

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