Historical insights into cytokines

Abstract

Cytokines affect nearly every biological process; these include embryonic development, disease pathogenesis, non-specific response to infection, specific response to antigen, changes in cognitive functions and progression of the degenerative processes of aging. In addition, cytokines are part of stem cell differentiation, vaccine efficacy and allograft rejection. This short insight focuses on the milestones in cytokine biology and how the various and often contradictory activities of these small, non-structural proteins affected the fields of inflammation and immunology. Multiple biological properties or pleiotropism is the hallmark of a cytokine. Today, the term "cytokine" encompasses interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. As of this writing, 33 cytokines are called interleukins, but many are part of families of related but distinct gene products. There are certainly over 100 separate genes coding for cytokine-like activities, many with overlapping functions and many still unexplored. Also discussed in this overview are the failures and successes of cytokines as therapeutic targets. A recent advance in the field has been that of differential cytokine production, which can be used to classify human disease as being "autoimmune" or "autoinflammatory" thus impacting on therapeutic interventions.

Figure 1

Cryopyrin Inflammasome. The function of the cryopyrin inflammasome is to activate inactive procapsase-1 into an active heterodimeric enzyme. Active caspase-1 cleaves the N-terminal 116 amino acids from the inactive IL-1β precursor. The inflammasome is a complex of interacting intracellular proteins and each component assembles to form the complex. Cryopyrin (also known as NALP3) binds to procaspase-1 via CARD (caspase-1 recruitment domain) and the CARD on ASC (apoptosis-associated speck-like protein containing CARD) and its pyrin (PYR) domain. Cryopyrin is a large protein with four domains: PYR, a pyrin domain; NACHT (a domain found in NAIP, CIITA, HET-E and TP-1), NAD (NALP-associated domain) and LRR (Leucine Rich Repeats). Mutations in cryopyrin are associated with three autoinflammatory diseases (FCAS, MWS, NOMID) [–42]. Other proteins are part of the cryopyrin complex such as Cardinal (CARD Inhibitor of NFκB-Activating Ligands). The processing of pro-caspase-1 results in the formation of the active caspase-1 heterodimer and the cleavage of the IL-1β precursor. The enzymatic processing of the IL-1β precursor by caspase-1 may take place in the cytosol or in the secretory lysosomes [43] or both.

Figure 2

Four examples of cytokines and their receptors. A. TNF. TNFα is biologically active as a trimer. The TNF receptor is comprised of three chains (homotrimer) of either the TNF type 1 receptor (TNF-RI, also known as p55) [34] or a homotrimer of the type 2 receptor, not shown (also known as p75) [34] and initiates signal transduction. The cytoplasmic domains of the TNF R (I or II) contains death domains. B. IL-1. IL-1 binds to the type I IL-1 receptor (ligand binding chain) with a low affinity [7]. The IL-1 receptor accessory protein (IL-1RAcP) [44] is then recruited to form a high affinity heterodimer. The cytoplasmic domains of the IL-1 receptors (type I and IL-1RAcP) contain the Toll-IL-1 receptor (TIR) domains, which are essential for signaling [45]. The cytoplasmic domains of the IL-1 receptors share a high level of homology with the TLR and signaling is also similar. C. IL-2. IL-2 binds to the IL-2Rα chain with a low affinity [46, 47]. The signaling chain IL-2Rβ forms the dimeric complex. D. IL-6. Like IL-1 and TNF, IL-6 is a pleiotropic cytokine [48]. IL-6 first binds to the soluble IL-6 receptor. The soluble IL-6 receptor binds to two chains of the gp130 receptor initiating a signal.

Figure 3

Time-line of milestones in cytokine biology. The early work on cytokines focused on soluble factors that were active in vivo models such as fever in rabbits [49] [–52]. Colony stimulating factors (CSF), first reported by Leo Sachs and Donald Metcalf, interferon and migration inhibitory factor (MIF) [53] were some of the first cytokines studied in vitro. MNC, mononuclear cell factor, an inducer of PGE2 and collagenases [54] and catabolin [55] for breakdown of cartilage were studies focused on the role of soluble factors affecting cartilage in models of rheumatoid arthritis. LEM, leukocytic endogenous mediator, was studed primarily as an inducer of hepatic acute phase proteins [56, 57]. LAF (lymphocyte activating factor), a macrophage product first described by Gery and Waksman [4], was shown to be mediated by leukocytic pyrogen purified from human monocytes [52, 58]. TNF was initially described as a serum factor in animals injected with endotoxin [59]. Later, the endotoxin-induced macrophage product cachetin was purified and shown to be identical to TNF [60]. B-cell growth factors (BCGF) included several factors reviewed in [61]. IL-2 was originally described as T-cell growth factor [5]. IL-8 was the first chemokine [62, 63] of a very large family. The term IL-1β converting enzyme was changed to caspase-1 and the caspase family expanded.