Carol A. Feghali, Ph.D., and Timothy M. Wright, M.D.

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, E1109 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261

Received 11/06/96; Accepted 12/13/96; On-line 01/01/97

2. INTRODUCTION

Inflammation, the response of tissue to injury, is characterized in the acute phase by increased blood flow and vascular permeability along with the accumulation of fluid, leukocytes, and inflammatory mediators such as cytokines. In the subacute/chronic phase (hereafter referred to as the chronic phase), it is characterized by the development of specific humoral and cellular immune responses to the pathogen(s) present at the site of tissue injury. During both acute and chronic inflammatory processes, a variety of soluble factors are involved in leukocyte recruitment through increased expression of cellular adhesion molecules and chemoattraction. Many of these soluble mediators regulate the activation of the resident cells (such as fibroblasts, endothelial cells, tissue macrophages, and mast cells) and the newly recruited inflammatory cells (such as monocytes, lymphocytes, neutrophils, and eosinophils), and some of these mediators result in the systemic responses to the inflammatory process (e.g. fever, hypotension, synthesis of acute phase proteins, leukocytosis, cachexia). The soluble factors that mediate these responses (reviewed in ref. 1) fall into four main categories: (1) inflammatory lipid metabolites such as platelet activating factor (PAF) and the numerous derivatives of arachidonic acid (prostaglandins, leukotrienes, lipoxins), which are generated from cellular phospholipids; (2) three cascades of soluble proteases/substrates (clotting, complement, and kinins), which generate numerous pro-inflammatory peptides; (3) nitric oxide, a potent endogenous vasodilator, whose role in the inflammatory process has only recently begun to be explored; and (4) a group of cell-derived polypeptides, known as cytokines, which to a large extent orchestrate the inflammatory response, i.e. they are major determinants of the make-up of the cellular infiltrate, the state of cellular activation, and the systemic responses to inflammation. Most cytokines are multifunctional. They are pleiotropic molecules that elicit their effects locally or systemically in an autocrine or paracrine manner. Cytokines are involved in extensive networks that involve synergistic as well as antagonistic interactions and exhibit both negative and positive regulatory effects on various target cells.

This review will focus on inflammatory cytokines, including a description of their primary activities related to acute and chronic inflammation, and a discussion of their cell surface receptors.