The immune system is skilled in communication and designed to respond quickly, specifically and globally to protect an organism against foreign invaders and diseases. The major players in this process are cytokines and chemotactic cytokines called chemokines [1]. Cytokines have a key role in the signalling network between cells and are essential in generating and regulating the immune system. The cytokine superfamily includes interleukins (ILs), chemokines, colony-stimulating factors (CSF), interferons (IFNs), transforming growth factors (TGF) and tumor necrosis factor (TNF). Cytokines are redundant secreted proteins with growth, differentiation and activation functions that regulate and determine the nature of immune responses and control immune cell trafficking and the cellular arrangement of immune organs. Current evidence supports their role as multifunctional molecules in haematopoiesis, immunity, infectious diseases, tumorigenesis, homeostasis and tissue repair, cell growth and development. Cytokines are approximately 5 to 30 kDa peptides, proteins, or glycoproteins with a very short half-life and are able to act locally at Pico molar concentrations [2]. They may exert their action on cells secreting them (autocrine action), on nearby cells (paracrine action), or in specific conditions on distant cells (endocrine action) [3].

Chemokines, a subset of the cytokines having chemotactic properties, consist of 48 proteins classified into 4 groups (XCL, CCL, CXCL, and CX3CL) based on the position of two cysteine residues in their sequence. They bind to 19 G protein-coupled seven transmembrane receptors that form either homodimers or heterodimers. Similar to their ligands, chemokine receptors are classified into 4 groups, namely XCR, CCR, CXCR, and CX3CR. Each receptor can bind to several ligands of the same family and vice versa. Chemokines are involved in many biological processes including angiogenesis, tumor growth and metastasis, and leukocytes migration [4].

Ramani recently classified cytokines in three different classes depending on their functions. Cytokines may be ‘‘good’’ when stimulating the immune system to fight a foreign pathogen or attack tumors, or acting to reduce immune response, as well as assisting in the reduction of neuron inflammation in patients with multiple sclerosis by IFN-β. They may be ‘‘bad’’ when their expression enhances inflammatory responses and diseases. Such as for proinflammatory cytokines like IL-1, IL-6, TGF-β and TNF-α that are expressed early and sequentially and could amplify an inflammatory event. Cytokines could even be “deadly” when, as consequence of severe immune reaction, overproduction of immune cells and their activating compounds (cytokines) occur, resulting in a so called “cytokine storm” with potential multi-organ failure often causing patients death [5,6].

However, cytokine signalling circuits include multiple regulatory checkpoints which often involve feedback inhibition. In “normal” conditions, the process allows tissues to return to a relatively quiescent, non-inflammatory state of immunotolerance. Whereas proinflammatory cytokines alert the immune system to the presence of potential infection or danger. An imbalance in cytokine production or cytokine receptor expression can contribute to various pathological disorders including autoimmune diseases and cancer [7].

Evidence suggests the therapeutic value of restoring an optimal cytokine balance that could theoretically be achieved either by blocking pro-inflammatory or inducing/providing anti-inflammatory cytokines. Cytokine therapeutic intervention has been taken as an alternative for disease control and has been recently proven as a novel therapeutic approach in treating patients with advanced malignancies. Manipulation of the immune response in such a way showed in fact to generate appropriate immune effector cells resulting in solid tumors eradication, modulation of inflammatory and autoimmune disease, as well as to the control of “cytokine storms” [8].

The role of cytokines in autoimmune diseases have been widely studied. Over-production of proinflammatory cytokines, as well as the relative paucity of regulatory cytokines, contribute to the immunopathogenesis of these diseases and control of optimal cytokine balance may have therapeutic value. To date, the use of interferon to treat multiple sclerosis or vasculitis represents a good example in clinical practice. On the other hand, other approaches such as the administration of anti-inflammatory cytokines have been disappointing. Cytokine therapy has been tested for treatment of cardiac fibrosis, since pro-inflammatory and pro-fibrotic cytokines play central modulating roles in the remodelling cascades. However, systemic targeting of potent cytokines such as TNF-α, IFN-γ, and TGF-β by antibodies or receptor inhibitors have been challenging. Likely due to pleiotropic effects of these cytokines in healthy organs of the body [9].

A growing literature supports pro-inflammatory cytokine signalling between immune, glial and neural cells as a key factor involved in pain and suggests possible approaches to treat patients with chronic pain. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways [10].

Regarding the role of cytokines in cancer, several papers support their involvement in tumorigenic processes. Secreted by tumor cells and other cell types, including immune cells and stromal cells in the tumor microenvironment, chemokines can modulate immune cell trafficking and lymphoid tissue growth, thus regulating anti-tumor immunological responses in a spatiotemporal manner [11,12]. In this contest, IL-2 helps immune system cells to grow and divide more quickly. A humanized version of IL-2 is approved to treat advanced kidney cancer and metastatic melanoma. IL-2 can be used as a single drug treatment for these cancers, or it can be combined with chemotherapy or with other cytokines such as interferon-alfa [13].

A recent paper reported that IL-27, belonging to IL-12 cytokine family, exerts anti-tumor potential in several solid tumors, as well as hematologic malignancies. IL-27 showed to inhibit tumor growth and progression through direct and indirect mechanisms, such as inhibition of proliferation, angiogenesis, induction of apoptosis in tumor cells and anti-tumor immune response [14].

As consequence of ILs involvement in several diseases, their plasma levels can represent a marker for early diagnosis. IL-25, also known as IL-17, was found to be involved in inflammatory responses and showed a close relation to cardiovascular diseases such as coronary artery disease (CAD), one of the most fatal cardiovascular diseases with a high hospitalization rate and mortality. In particular, inflammatory response has been identified to participate in CAD acting on atherosclerosis and preliminary results showed a correlation between IL-25 serum increase, the severity of coronary stenosis and the occurrence of acute coronary syndrome (ACS) in CAD patients [15].

More recently, a “deadly” cytokine imbalance has also been suggested in the acute respiratory distress syndrome in patients with Corona Virus Disease 2019 (COVID-19). In the later stage of the disease, some COVID-19 patients may also develop multiple organ failure that seems to be often associated with a high mortality rate. One of the most important mechanisms underlying the deterioration of the disease is a cytokine storm. Among the attempts to treat these late stage individuals, experimental use of drugs inhibiting IL-6, a proinflammatory cytokine involved in proliferative and differentiation process of T and B lymphocytes, seems to be the most promising at present [16].

Cytokine and chemokine networking are extremely complex. They are composed by a large number of interacting ligands, receptors, and regulatory proteins engaged in complex cellular processes. More than four decades of research supports the role of cytokines and chemokines as key elements in homeostasis and diseases through their pivotal control in inflammation and immunity.

Research has achieved considerable progress in identifying the role and effect of cytokines and chemokines in every aspect of human health.  However, efforts are still needed to characterize the use of cytokines themselves or identify drugs able to control their production and effects and to provide clinicians with more effective therapies.

I’d like to thank Dr Angelo Guglielmotti, Angelini Pharma, and Dr Cristina Bartella, ToxHub Associate, for reviewing the manuscript and for the support in its realization. Searching PubMed with ‘cytokine’ and ‘chemokine’ identifies more then 500 000 articles: the author apologizes to those whose excellent work they have been unable to cite due to space limitations.