Cell-cell contact in chronic inflammation: the importance to cytokine regulation in tissue destruction and repair

Abstract

In many chronic diseases, inflammation is characterized by the influx into the target tissue of migratory cells such as T and B lymphocytes, dendritic cells, neutrophils and mononuclear phagocytes. This influx of inflammatory cells in the target tissue is associated with the proliferation of invading and resident cells and frequently with destruction and remodeling of the extracellular matrix. In the joint structures, the destruction of the organic phase is due to proteases (mainly MMP whose activity is controlled by specific inhibitors) and the resorption of the inorganic phase of bone, mainly due to the action of the receptor activator of NF-kB and its ligand (RANK-RANKL) and prostanoids. The expression of these proteases and their inhibitors is regulated by different types of stimuli, including soluble factors (i.e., cytokines, hormones), contact with extracellular matrix components and direct cellular interactions [1-2]. In pathologic conditions, the production of cytokines and MMP by infiltrating and resident tissue cells escapes regulatory mechanisms. The activity of proinflammatory cytokines is counterbalanced by numerous mechanisms of which cytokine inhibitors — IL-1 receptor antagonist (IL-1Ra), TNF soluble receptors (TNFsR) — and tissue inhibitor of MMP (TIMP) are examples. It is generally acknowledged that the imbalance between cytokines and their respective inhibitors is responsible for the persistence of chronic inflammatory conditions and maybe even necessary for their initiation. There is now considerable evidence that cytokines such as TNFα and IL-1 are involved in many diseases resulting in tissue destruction. This has been demonstrated by human clinical trials in rheumatoid arthritis (RA) (for review see [4-8]). Cytokine blockade in the clinic has also proved useful in many other diseases including juvenile idiopathic arthritis, Crohn’s disease, spondyloarthropathy, vasculitis and psoriasis [9-16]. The above cytokines are also involved in the pathogenesis of several other diseases including multiple sclerosis (MS) [17, 18], systemic lupus erythematosus (SLE) [19, 20], and atherosclerosis [21, 22].KeywordsRheumatoid ArthritisMultiple SclerosisSystemic Lupus ErythematosusTNFa ProductionTNFa InhibitorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.