Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance?

Arthritis Research & Therapy Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance? Carlo Chizzolini1, Jean-Michel Dayer2 and Pierre Miossec3 Corresponding author: Carlo Chizzolini 0 Department of Immunology and Rheumatology, Hospital Edouard Herriot, University of Lyon , 69437 Lyon , France 1 School of Medicine, University of Geneva , rue Michel Servet 1, 1211 Geneva 14 , Switzerland 2 Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva University Hospital , 1211 Geneva 14 , Switzerland Biological systems have powerful inbuilt mechanisms of control intended to maintain homeostasis. Cytokines are no exception to this rule, and imbalance in cytokine activities may lead to inflammation with subsequent tissue and organ damage, altered function, and death. Balance is achieved through multiple, not mutually exclusive, mechanisms including the simultaneous production of agonist and antagonistic cytokines, expression of soluble receptors or membrane-bound nonsignaling receptors, priming and/or reprogramming of signaling, and uncoupling of ligand/receptor pairing from signal transduction. Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production. - Introduction To explore the complex regulation of cytokine activities it may be of help to bear in mind the example of rheumatoid arthritis (RA). A major step forward in RA treatment was achieved when it became possible to control disease manifestations such as joint destruction by blocking TNF. This could indicate that a single cytokine, in this case TNF, drives unopposed a series of events that lead to inflammation and destruction. The situation is less simple inside the joint, however, where proinflammatory cytokines co-exist alongside their endogenous inhibitors. This is a consequence of ongoing processes in which proinflammatory stimuli induce their anti-inflammatory counterparts and the imbalance between the two results in disease. The cytokine network is a homeostatic system that may be comparable with the acid/base equilibrium. The biological activity of any cytokine in biological fluids can be interpreted correctly only by taking into account the activities of other synergistic or antagonistic cytokines, of their respective inhibitors, and the extent to which each cytokine receptor is expressed. Interactions between intracellular signals modulate further cytokine activities. In addition, cell types with polarized patterns of cytokine production contribute to the balance. Owing to their potent activities in many different processes including cell growth and differentiation, organ development, inflammation, immune response, and repair processes aiming at homeostasis cytokine activities have to be tightly controlled. Since one of the main functions of cytokines is to mediate interactions between the immune and inflammatory responses, it is thought that chronic immunoinflammatory diseases might be caused in part by the uncontrolled production of cytokines. Furthermore, depending on the stage of inflammation or the biological effect under scrutiny, the same cytokine may have proinflammatory or antiinflammatory activities. Many different mechanisms of regulation have been identified affecting both cells and soluble mediators (Table 1). The present review describes the key levels of imbalance that have been associated with chronic inflammation and tissue destruction. This has to be integrated in general processes of disease initiation through the innate and adaptive immune responses ending in tissue and organ damage (Figure 1). Balance in cytokines Balance between IL-1 and IL-1 natural antagonists Amongst the most powerful proinflammatory cytokines, IL-1 stands out as a paradigmatic example of fine-tuned regulation of biological activities through a complex system of ligands with agonist and antagonist functions, as well as signaling CCR = CC-family chemokine receptor; DARC = Duffy antigen receptor for chemokines; EAE = experimental allergic encephalomyelitis; Foxp3 = forkhead box p3; IFN = interferon; IL = interleukin; IL-1R = IL-1 receptor; IL-6R = IL-6 receptor alpha; IL-1Ra = IL-1 receptor antagonist; NF = nuclear factor; RA = rheumatoid arthritis; RANTES = regulated on activation, normal T-cell expressed and secreted; SIGIRR = single immunoglobulin IL-1-related receptor; sIL-6R = soluble IL-6R; SOCS = suppressors of cytokine signaling; STAT = signal transducer and activator of transcription; TGF = transforming growth factor beta; Th = T-helper type; TNF = tumor necrosis factor; Treg = T cell with regulatory function; Wnt = wingless integration site. Balance in cytokine activities according to biological processes IL-18 / IL-18 binding protein IL-22 / IL-22 binding protein IL-13 / IL-13 receptor alpha CXCLELR+ / CXCLELR IL-1 / IL-1 receptor antagonist, IL-1 receptor II, soluble IL-1 receptor I, soluble IL-1 receptor II TNF / soluble TNF receptor I, soluble TNF receptor II Tissue repair and remodeling Transforming growth factor beta / TNF Several proinflammatory chemokines (CXC and CC) / Duffy antigen receptor for chemokines Several proinflammatory chemokines (CC not CXC) / D6 CCL19, CCL21, CCL25, CXCL13 / CCX-CKR Chemerin 9 / chemerin 15 Th1 cells / Th2 cells Th17 cells /Th2 cells Th17 cells / T cells with regulatory function T cells with regulatory function / Th1, Th2, Th17 cells Transforming growth factor beta / IL-6 + T-cell growth factor beta Adiponectin / leptin, vistatin, resistin In view of the pleiotropic actions of cytokines, the table presents a far from complete view of possible opposing activities of cytokines and their ligands. The back slash (/) separates the opposing molecules in respect of a given biological activity. RANKL, receptor activator of NKB ligand; WNT, wingless integration site. and nonsignaling receptors (Figure 2). First of all, a natural ligand of IL-1 receptors IL-1 receptor antagonist (IL-1Ra) prevents recruitment of the accessory protein needed to signal, thus acting as a competitor to IL-1 [1]. Interestingly, IL-1Ra is preferentially produced by monocytes/macrophages stimulated by anti-inflammatory cytokines (see below). Second, two IL-1 receptors (Il-1RI and IL-1RII) are expressed at the surface of many cell types. An important functional difference, however, exists between the two receptors. Indeed, in contrast to IL-1RI, which transduces the signal, IL-1RII does not transduce and acts as a decoy receptor. Furthermore, both receptors may be shed from the cell surface by matrix metalloproteinases, and by binding to IL-1 or IL-1Ra soluble receptors may modulate their bioavailability, ultimately affecting cell responses. One of the many members of the IL-1 family, IL-1F5, also has inhibitory activities [2]. Some patients have autoantibodies to IL-1 and these may also play a role by blocking I (...truncated)