Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: a promising inhibitory strategy.

SARS-Cov-2 infection causes local and systemic inflammation mediated by pro-inflammatory cytokines and COX-2 eicosanoid products with metabolic dysfunction and tissue damage that can lead to patient death. These effects are primarily induced by IL-1 cytokines, which are involved in the elevation of hepatic acute phase proteins and fever. IL-1 has a broad spectrum of biological activities and participates in both innate and acquired immunity. In infections, IL-1 induces gene expression and synthesis of several cytokines/chemokines in both macrophages and mast cells (MCs). The activation of MCs triggers the secretion of mediators stored in the granules, and the de novo synthesis of pro-inflammatory cytokines. In microorganism infections, the release of IL-1 macrophage acts on adhesion molecules and endothelial cells leading to hypotension and septic shock syndrome. IL-1 activated by SARS-CoV-2 stimulates the secretion of TNF, IL-6 and other cytokines, a pro-inflammatory complex that can lead to cytokine storm and be deleterious in both lung and systemically. In SARS-CoV-2 septic shock, severe metabolic cellular abnormalities occur which can lead to death. Here, we report that SARS-CoV-2 induces IL-1 in macrophages and MCs causing the induction of gene expression and activation of other pro-inflammatory cytokines. Since IL-1 is toxic, its production from ubiquitous MCs and macrophages activated by SARS-CoV-2 can also provokes both gastrointestinal and brain disorders. Furthermore, in these immune cells, IL-1 also elevates nitric oxide, and the release of inflammatory arachidonic acid products such as prostaglndins and thromboxane A2. All together these effects can generate cytokine storm and be the primary cause of severe inflammation with respiratory distress and death. Although, IL-1 administered in low doses may be protective; when it is produced in high doses in infectious diseases can be detrimental, therefore, IL-1 blockade has been studied in many human diseases including sepsis, resulting that blocking it is absolutely necessary. This definitely nurtures hope for a new effective therapeutic treatment. Recently, two interesting anti-IL-1 cytokines have been widely described: IL-37 and IL-1Ra. IL-37, by blocking IL-1, has been observed to have anti-inflammatory action in rodents in vivo and in transfected cells. It has been reported that IL-37 is a very powerful protein which inhibits inflammation and its inhibition can be a valid therapeutic strategy. IL-37 is a natural suppressor of inflammation that is generated through a caspase-1 that cleaves pro-IL-37 into mature IL-37 which translocates to the nucleus and inhibits the transcription of pro-inflammatory genes; while IL-1Ra inhibits inflammation by binding IL-1 to its IL-1R (receptor). We firmly believe that blocking IL-1 with an anti-inflammatory cytokine such as IL-37 and/or IL-1Ra is an effective valid therapy in a wide spectrum of inflammatory disorders including SARS-CoV-2-induced COVID-19. Here, we propose for the first time that IL-37, by blocking IL-1, may have an important role in the therapy of COVID-19.

SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines.

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic coronavirus disease 2019 (COVID-19). In humans, SARS-CoV-2 infection leads to acute respiratory distress syndrome which presents edema, hemorrhage, intra-alveolar fibrin deposition, and vascular changes characterized by thrombus formation, micro-angiopathy and thrombosis. These clinical signs are mediated by pro-inflammatory cytokines. In recent studies it has been noted that COVID-19 pandemic can affect patients of all ages, including children (even if less severely) who were initially thought to be immune. Kawasaki disease is an autoimmune acute febrile inflammatory condition, which primarily affects young children. The disease can present immunodeficiency with the inability of the immune system to fight inflammatory pathogens and leads to fever, rash, alterations of the mucous membranes, conjunctiva infection, pharyngeal erythema, adenopathy, and inflammation. In the COVID-19 period, virus infection aggravates the condition of Kawasaki disease, but it has also been noted that children affected by SARS-V-2 may develop a disease similar to Kawasaki's illness. However, it is uncertain whether the virus alone can give Kawasaki disease-like forms. As in COVID-19, Kawasaki disease and its similar forms are mediated by pro-inflammatory cytokines produced by innate immunity cells such as macrophages and mast cells (MCs). In light of the above, it is therefore pertinent to think that by blocking pro-inflammatory cytokines with new anti-inflammatory cytokines, such as IL-37 and IL-38, it is possible to alleviate the symptoms of the disease and have a new available therapeutic tool. However, since Kawasaki and Kawasaki-like diseases present immunodeficiency, treatment with anti-inflammatory/immunosuppressant molecules must be applied very carefully.

Interrelationship between inflammatory cytokines (IL-1, IL-6, IL-33, IL-37) and acquired immunity.

It is now well-known that interleukins (ILs) play a pivotal role in shaping innate immunity: inflammatory ILs are responsible for all innate aspects of immune response, from the very first vascular reactions to the chronic non-specific response to inflammation; while anti-inflammatory ILs are responsible for keeping adaptive immunity at bay. The interactions between ILs and adaptive immunity have been long considered secondary to the effects on the innate immune system, but in recent years it has appeared more clearly that IL direct interactions with adaptive immunity are extremely important both in physiologic and pathologic immune response. In the present review we analyze the role of inflammatory ILs (IL-1, IL-6, IL-33 and IL-37) on adaptive immunity and briefly discuss the possible therapeutic perspectives of IL-blockade in adaptive immunity disorders.

CAR-T cell therapy causes inflammation by IL-1 which activates inflammatory cytokine mast cells: anti-inflammatory role of IL-37.

Chimeric antigen receptor (CAR) T cells are genetically modified T cells that act against cancer. When CAR-T cells are administered they can trigger inflammatory cytokines and increase toxicity. Interleukin (IL)-1 is the classic cytokine that mediates inflammatory reactions including those that occur in CAR-T-cell therapy. IL-1 also induces IL-33 in mast cells (MCs), amplifying the allergic reaction. IL- 37 (ILF7) is an IL-1 family member which binds IL-18 receptor alpha (IL-18Rα) chain and suppresses innate and acquired immunity. IL-37 is an anti-inflammatory cytokine which inhibits pro-inflammatory cytokines including IL-1 and IL-33. Here, we hypothesize that inflammation and toxicity generated in tumor CAR-T therapy could be inhibited by IL-37, contributing to an improvement in the treatment of tumors with CAR-T therapy.

Stimulated mast cells release inflammatory cytokines: potential suppression and therapeutical aspects.

Mast cells (MCs) are derived from bone marrow precursors and are immune cells involved in acute and chronic inflammation. MCs are ubiquitous and play a crucial role in innate and acquired immunity. They are activated through cross-linking of their surface high affinity receptors (FcεRI), leading to immediate secretion of stored inflammatory mediators, and late production and release of pro-inflammatory cytokines/chemokines without degranulation. Therefore, MCs are important in inflammatory responses. Members of the interleukin (IL)-1 cytokine family, such as IL-1 and IL-33, and various antigens markedly increase IL-1 and tumor necrosis factor (TNF) expression and secretion from MCs. One of the latest cytokines is IL-33, an IL-1 family member acting via its ST2/IL-1R4, which has been shown to regulate MCs. IL-1 and IL-33 are cytokines found to be implicated in many inflammatory disorders including rheumatoid arthritis, atherosclerosis and psoriasis. In general, IL-1 family member cytokines play a pro-inflammatory role and increase the pathological state. IL-37 is a member of the IL-1 family with anti-inflammatory activity through inhibition of pro-inflammatory cytokines. IL-37 particularly suppresses IL-1-mediated innate inflammatory response, but also acts on the acquired immune response. IL-37 is activated by pro-inflammatory agents and cytokines, playing a protective role against inflammation. This cytokine is a natural regulator of immunity and is a therapeutic promise against inflammatory diseases. Since IL-1 is produced by and activates MCs to release IL-33 and TNF, here we hypothesize that MCs can be inhibited by IL-37 and therefore reduce their pro-inflammatory activity. However, the maturation, transport and secretion of IL-37 remain to be clarified.

IL-33 mediates allergy through mast cell activation: Potential inhibitory effect of certain cytokines.

Mast cells (MCs) are hematopoietic immune cells commonly found in adjacent to blood vessels in the lamina propria of airway mucosa. They are important in allergic reactions since the cross-linking of their surface high affinity receptor FceRI induces activation of these cells, and provokes the synthesis, degranulation and release of inflammatory mediators including arachidonic acid-derived eicosanoids (de novo synthesized), stored enzyme mediators, and inflammatory TH1 and TH2 cytokines, and chemokines. Interleukin (IL)-33 participates in innate and adaptive immunity and inflammation and, acting on CD34+ cells, causes MC differentiation and maturation. IL-33 is generated by activated immune cells, and activates MCs which degranulate and release pro-inflammatory mediators. IL-33 is very important in mediating allergic inflammation and can be induced by IL-1 beta. It is also called "alarmin" and is an inflammatory cytokine IL-1 family member, expressed from mocytes and MCs, which binds its receptor ST2, provoking its release after cell damage. MC-derived allergic compounds in response to IL-33 is critical to innate type 2 immunity. IL-37 is expressed by immune and non-immune cells after pro-inflammatory stimulus. IL-37, an anti-inflammatory cytokine, binds IL-18Ra and suppresses pro-inflammatory IL-1 beta released by activated immune cells such as macrophages. Here, we hypothesize that pro-inflammatory IL-1 family member cytokines released by activated MCs, mediating inflammatory allergic phenomenon, can be suppressed by IL-37.

Impact of mold on mast cell-cytokine immune response.

Molds include all species of microscopic fungi, the spores of which are small molecules, ubiquitous, mostly found in soil with higher rainfall and high humidity, in the atmosphere of urban and rural settings and in decaying vegetation. They originate from pathogenic fungi and have a crucial role in inflammatory response, causing a broad range of diseases. Immune suppressed subjects may develop mycoses caused by opportunistic common pathogenic fungi. Mast cells (MCs) are immune cells involved in the pathophysiology of infected skin, lung, and organs, where there is an increase of angiogenesis. Airways fungi infections can induce allergic lung disease mediated by MCs and other immune cells. In addition, fungal infection may cause and/or aggravate asthma inflammation. Spores are able to navigate in the airways of the lung and can be recognized trough toll-like receptor (TLR) signaling by the innate immune cells including MCs. Activated MCs release preformed mediators including histamine, proteases (tryptase, chimase), pro-inflammatory cytokines/chemokines and they also generate arachidonic acid products. MCs activated by fungi provoke an increases of PGD2 levels and lead to hypersensitivity diseases which present signs such as irritation of the respiratory tract and eyes, recurrent sinusitis, bronchitis, cough and neurological manifestations including fatigue, nausea, headaches and brain fog. Therefore, fungi activate the innate immune response through the TLRs, leading to the release of myeloid differentiation factor 88 (MyD88) which, with a series of cascade reactions, induces the stimulation of AP-1 and NF-kB with subsequent activation of inflammatory IL-1 family members. Here, we report that fungi can activate MCs to secrete pro-inflammatory cytokines which may be inhibited by IL-37, a new anti-inflammatory IL-1 family member.

Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37.

It has been observed that acute stress causes the activation of TH1 cells, while TH2 cells regulate and act on chronic inflammation. Fibromyalgia (FM) is a chronic, idiopathic disorder which affects about twelve million people in the United States. FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. The mechanism of induction of muscle pain and inflammation is not yet clear. In FM there is an increase in reactivity of central neurons with increased sensitivity localized mainly in the CNS. Mast cells are involved in FM by releasing proinflammatory cytokines, chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs and its level is higher in FM. The inhibition of pro-inflammatory IL-1 family members and TNF by IL-37 in FM could have a therapeutic effect. Here, we report for the first time the relationship between MCs, inflammatory cytokines and the new anti-inflammatory cytokine IL-37 in FM.

Mast cell in innate immunity mediated by proinflammatory and antiinflammatory IL-1 family members.

Innate immunity consists of physical and chemical barriers which provide the early defense against infections. Innate immunity orchestrates the defense of the host with cellular and biochemical proteins. Mast cells (MCs) are involved in innate and adaptive immunity and are the first line of defense which generates multiple inflammatory cytokines/chemokines in response to numerous antigens. MC-activated antigen receptor Fc-RI provokes a number of important biochemical pathways with secretion of numerous vasoactive, chemoattractant and inflammatory compounds which participate in allergic and inflammatory diseases. MCs can also be activated by Th1 cytokines and generate pre-formed and de novo inflammatory mediators, including TNF. IL-37 is an anti-inflammatory cytokine which binds IL-18R-alpha chain and reduces the production of inflammatory IL-1 family members. IL-37 down-regulates innate immunity by inhibiting macrophage response and its accumulation and reduces the cytokines that mediate inflammatory diseases. Here, we discuss the relationship between MCs, innate immunity, and pro-inflammatory and anti-inflammatory cytokines.

Mast cell, pro-inflammatory and anti-inflammatory: Jekyll and Hyde, the story continues.

IL-1 family members include inflammatory and anti-inflammatory cytokines. They can be beneficial or detrimental, not only in cancer, but also in inflammatory conditions. Mast cells (MCs) originate from CD34+/CD117+/CD13+ pluripotent hematopoietic stem cells, express c-Kit receptor (c-Kit-R), which regulates the proliferation and sustain the survival, differentiation and maturation of MCs. They are immune cells involved in innate and adaptive immunity, allergy, autoimmunity, cancer and inflammation. MCs along with T cells and macrophages release interleukin (IL)-10, which is a pleiotropic immunoregulatory cytokine with multiple biological effects. IL-10 inhibits Th1 inflammatory cells, in particular TNF mostly generated by macrophages and MCs, and down-regulates IFN-γ, IL-1 and IL-6. IL-37 is a family member cytokine which binds IL-18 receptor α chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33 and nitric oxide (NO). IL-37 similar to IL-10 inhibits MC inflammatory cytokines in several disorders, including asthma, allergy, arthrtitis and cancer. Here we report a study comparing IL-10 with IL-37, two anti-inflammatory cytokines.

Fibromyalgia and bipolar disorder: extent of comorbidity and therapeutic implications.

Fibromyalgia (FM) is a syndrome that affects muscles and soft tissues. Presenting symptoms include chronic muscle pain, fatigue, sleep problems and psychological symptoms, including depression and anxiety. There exists strong evidence of a comorbidity between FM and Bipolar Disorder (BD). In this study, papers from 2006 to February 2016 that examined the comorbidity and etiological similarities of FM and BD were reviewed, as well as the therapeutic implications of these findings. The reviewed articles showed that an adequate psychiatric screening for BD is recommended in FM patients with depressive symptoms, in order to decrease administration of antidepressants for BD, due to the lack of proven efficacy, and to limit antidepressant-induced mania. Alternative therapies, such as agomelatine, memantine and psychotherapic treatment should be considered.

Alexithymia and its relationships with inflammatory response mediated by IL-1 family members.

The major aim of this study is to provide a review of the research studies regarding the clinical link between alexithymia and interleukins (IL). We performed a search for the relevant literature by using search terms as "alexithymia" combined with "interleukin or IL". A total of 9 original research studies were identified and included. Alexithymia was found to be prevalent in inflammatory response and associated with inflammatory cytokines. Our review emphasized for the first time the relationships of alexithymia with inflammatory response mediated by IL-1 family members. Therefore, the screening of alexithymic traits and the administration of appropriate psychological and psychotherapeutical interventions should be integral parts of disease management programs. Supplying such interventions will probably help with prevention of the development of the disease and/or its exacerbation by improving the quality of life of alexithymic individuals.

ENOX2 (or tNOX): a new and old molecule with cancer activity involved in tumor prevention and therapy.

Cancer includes a number of related diseases due to abnormal cell proliferation that spreads to nearby tissues. Many compounds (physical, chemical and biological) have been used to try to halt this abnormal proliferation, but the therapeutic results are poor, due also to the side effects. It has been reported that ecto-nicotinamide adenine dinucleotide oxidase di-sulfide-thiol exchanger 2 (ENOX2), also known as tumor-associated nicotinamide adenine dinucleotide oxidase (tNOX), was found to be located on the cancer cell surface, essential for cancer cell growth. Capsaicin and other anti-oxidants are capable of inhibiting tNOX, causing apoptosis of cells, exerting anti-tumor activity. It is interesting that some authors reported that ENOX2 is present in the serum of cancer patients several years before the clinical symptoms of the tumor. However, this result has to be confirmed. In this article we discuss ENOX2 and its inhibition as a hope of improving cancer therapy.

Mast cell and cancer with special emphasis on il-37 an anti-inflammatory and inhibitor of innate immunity: new frontiers.

Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cancer cells. MCs can promote both neoangiogenesis and tumor growth. They increase in the stroma of certain tumors where they can be recruited by tumor-derived chemoattractants, such as monocyte chemotactic protein-1 (MCP-1), RANTES and stem cell factor (SCF) to selectively secrete inflammatory molecules including chemical mediators and cytokines (TNF, IL-6 and IL-1). However, MC differentiation pathways and heterogeneity in cancer are still poorly understood. Human interleukin 1 (IL-1) plays a pivotal role in the pathogenesis of many diseases and functions, including host response to microbial invasion, injury inflammatory processes, immunologic challenges and cancer. Inflammation around the tumor includes the infiltration of mast cells and facilitates cancer growth. MCs are activated by IL-1 which can be produced by certain cancer cells and stimulate the stromal cells to selectively release IL-6, contributing to the development of Th-17 cells and increasing inflammation. IL-37, mainly generated by macrophage cell line, is an IL-1 family member which binds IL-18 receptor α (IL-18Rα) chain, and acts as a natural inhibitor of immune responses. IL-37 down-regulates cJun induced by IL-1, pro-inflammatory signals and reduces the expression of the mitogen-activated protein kinase (MAPK) p38α, STAT transcription factors and p53, affecting cellular differentiation and proliferation. In the present study we report the relationship between inflammatory mast cells, cancer and the beneficial effect of IL-37.