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Cytokine regulation of cellular adhesion molecule expression in inflammation

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Abstract

Cellular adhesion molecules (CAMs) play an essential role in tethering circulating leukocytes to the vascular endothelium at sites of inflammation. They are also instrumental in enabling leukocytes to transmigrate from blood vessels into adjacent inflamed tissues. In the absence of signals to stimulate expression of CAMs, the adhesive forces between leukocytes and the vascular endothelium are below the threshold level required to tether leukocytes. Research in the last decade has shown that several cytokines, including tumour necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β), potently increase the expression of many CAMs and thus increase the adhesiveness between leukocytes and the endothelium. The CAM-inducing activity of these cytokines is therefore crucial to the regulation of inflammatory processes. Overactivation of CAM expression is linked to a number of acute and chronic inflammatory conditions, and has led to the rationale of antagonising cytokine activity and/or CAM expression in order to treat these conditions. The potential application of ‘adhesion’ antagonists for the therapy of acute/chronic inflammatory conditions is briefly discussed.

Section snippets

Cellular adhesion molecules

The process of inflammation is central to protection of the host against infectious, and thus potentially harmful, micro-organisms, e.g., bacteria. In general, leukocytes circulating in the blood are drawn to sites of tissue injury or infection by chemoattractant gradients. However, other mechanisms are required to retard and eventually halt the movement of leukocytes in order that they can exit the blood vessel and migrate into the affected areas. The major mechanism involved in arrest of

Cytokine stimulation of CAM expression

In the early 1980 s, proinflammatory cytokines such as TNF-α, IL-1α, and IL-1β and gram-negative bacterial endotoxins (lipopolysaccharide, LPS) were demonstrated to directly stimulate increased leukocyte adhesion in cultured endothelial cells [19], [20]. Their stimulatory effect was much greater in amplitude than that of other previously studied leukocyte activators, such as leukotrienes, activated complement components, and chemotactic peptides, and has been shown to result in firm attachment

Effect of cytokine action on selectin expression

The selectins play a critical role in the migration of leukocytes to sites of inflammation by mediating the initial attachment and rolling of leukocytes on the vascular endothelium prior to integrin-dependent arrest and extravasation [1], [2], [3], [4], [5], [6], [8], [9]. Both E- and P-selectins on the endothelium probably participate in the initiation of leukocyte rolling [21]. E-selectin is not expressed on unstimulated (resting) endothelial cells in vitro, but is induced in response to

Effect of cytokine action on integrin receptors

Integrins are constitutively expressed on leukocytes, but are only able to form adhesive contacts with other cells following activation to produce structural and affinity changes in the external integrin moieties, in particular the I-domains which include binding sites for Ig-like addressin receptors [10], [11], [14], [37]. Activation appears to be a complex process involving divalent cations and stimuli transmitted through both integrins and non-integrin surface molecules resulting in

Mechanisms of adhesion molecule inductions

That many cellular adhesion molecules are induced by proinflammatory cytokines suggests that a common mechanism leading to CAM gene transcription is triggered. IL-1s and TNFs mediate their actions via distinct cell surface receptors, but downstream signalling pathways overlap considerably and involve common transcription factors. It is now clear that NF-κB is a crucial factor in both IL-1 and TNF mediated inducibility of adhesion molecules, including E-selectin, ICAM-1, VCAM-1 and MAdCAM-1 [60]

Potential therapeutic interventions for adhesion molecule-mediated inflammation

An inflammatory response begins when cells in damaged/infected tissues call for ‘help’ by secreting chemical mediators and cytokine that activate the endothelium of local blood vessels. In the majority of situations this lead to infiltration of affected tissues by activated leukocytes, a localised inflammatory reaction, tissue repair and resolution of infections. However, occasionally, and particularly in cases of massive tissue damage or overwhelming infections, the inflammatory reaction gets

Acknowledgments

I am indebted to Mrs Jenni Haynes for her expert typing of this manuscript.

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