Characterization of IL-10 Family of Cytokines in Acute and Convalescent COVID-19 Individuals.

Cytokines are major players in orchestrating inflammation, disease pathogenesis, and severity during COVID-19. Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses to various inflammatory and infectious diseases. However, the role of the IL-10 family of cytokines in COVID-19 remains elusive. Hence, we determined the plasma levels of the IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, and IL-24) in 7 groups of COVID-19 individuals, based on days since real-time reverse transcriptase-polymerase chain reaction confirmation of SARS-CoV-2 infection. Our data show that the levels of IL-10, IL-19, IL-20, IL-22, and IL-24 cytokines decreased from days 15-30 to days 61-90 and plateaued thereafter. Severe COVID-19 patients exhibit increased plasma levels of IL-10, IL-19, IL-20, IL-22, and IL-24 compared to mild patients. Thus, our study provides evidence of alterations in the plasma levels of the IL-10 family of cytokines in convalescent COVID-19 individuals.

A comprehensive review of IL-26 to pave a new way for a profound understanding of the pathobiology of cancer, inflammatory diseases and infections.

Cytokines are considered vital mediators of the immune system. Down- or upregulation of these mediators is linked to several inflammatory and pathologic situations. IL-26 is referred to as an identified member of the IL-10 family and IL-20 subfamily. Due to having a unique cationic structure, IL-26 exerts diverse functions in several diseases. Since IL-26 is mainly secreted from Th17, it is primarily considered a pro-inflammatory cytokine. Upon binding to its receptor complex (IL-10R1/IL-20R2), IL-26 activates multiple signalling mediators, especially STAT1/STAT3. In cancer, IL-26 induces IL-22-producing cells, which consequently decrease cytotoxic T-cell functions and promote tumour growth through activating anti-apoptotic proteins. In hypersensitivity conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis and allergic disease, this cytokine functions primarily as the disease-promoting mediator and might be considered a biomarker for disease prognosis. Although IL-26 exerts antimicrobial function in infections such as hepatitis, tuberculosis and leprosy, it has also been shown that IL-26 might be involved in the pathogenesis and exacerbation of sepsis. Besides, the involvement of IL-26 has been confirmed in other conditions, including graft-versus-host disease and chronic obstructive pulmonary disease. Therefore, due to the multifarious function of this cytokine, it is proposed that the underlying mechanism regarding IL-26 function should be elucidated. Collectively, it is hoped that the examination of IL-26 in several contexts might be promising in predicting disease prognosis and might introduce novel approaches in the treatment of various diseases.

Synthetic interleukin 22 (IL-22) signaling reveals biological activity of homodimeric IL-10 receptor 2 and functional cross-talk with the IL-6 receptor gp130.

Cytokine signaling is transmitted by cell-surface receptors that function as biological switches controlling mainly immune-related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP and mCherry nanobodies fused to transmembrane and intracellular domains of cytokine receptors that phenocopy cytokine signaling induced by nonphysiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 (IL-22) signals via both IL-22 receptor α1 (IL-22Rα1) and the common IL-10R2, belongs to the IL-10 cytokine family, and is critically involved in tissue regeneration. Here, IL-22 SyCyRs phenocopied native IL-22 signal transduction, indicated by induction of cytokine-dependent cellular proliferation, signal transduction, and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which previously was considered not to induce signal transduction, led to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) constructs could form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we have demonstrated that IL-22 signaling can be phenocopied by synthetic cytokine receptors, identified a functional IL-10R2 homodimeric receptor complex, and uncovered broad receptor cross-talk of IL-22Rα1 and IL-20R2 with gp130.

The IL-20 Cytokine Family in Rheumatoid Arthritis and Spondyloarthritis.

This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.

Diminished circulating plasma and elevated lymph node culture supernatant levels of IL-10 family cytokines in tuberculous lymphadenitis.

BACKGROUND: IL-10 family cytokines are associated with the host immune response to pulmonary tuberculosis (PTB), but their association with host response in tuberculous lymphadenitis (TBL) is not known. METHODS: Hence, we examined the circulating levels of the whole panel of IL-10 family cytokines in TBL (n = 44) and compared them to the levels in PTB (n = 44) and healthy control (HC, n = 44) individuals. We also assessed the pre and post-treatment cytokine levels in TBL individuals following the completion of anti-tuberculosis treatment (ATT). Next, we also compared the levels of IL-10 family cytokine in circulation versus lymph node (LN) culture supernatants in a subset of TBL individuals (n = 22). Finally, we also measured the levels of IL-10 family cytokines in tuberculosis antigen (purified protein derivative, PPD) stimulated and unstimulated LN culture supernatants. RESULTS: TBL individuals exhibit significantly decreased levels of IL-10, IL-19, IL-20, IL-24, IL-28B and IL-29 in the circulation when compared to PTB (except IL-10) and HC (except IL-20 and IL-28B) and significantly increased levels of IL-22 when compared to PTB individuals. Following ATT, TBL individuals exhibit significantly elevated levels of IL-10, IL-19, IL-20, IL-24, IL-28B and IL-29 and significantly diminished levels of IL-26. Similarly, TBL individuals also exhibited significantly increased levels of IL-10, IL-19, IL-20, IL-24, IL-28A and IL-29 in LN culture supernatants compared to plasma and significantly decreased levels of IL-22. This was associated with enhanced levels of IL-19, IL-20, IL-24, IL-28B and IL-29 upon PPD stimulation of LN cultures. CONCLUSIONS: Therefore, we demonstrate that TBL is associated with significantly diminished plasma and elevated LN culture supernatant levels of most of the IL-10 family cytokines. This to our knowledge is the first comprehensive examination of IL-10 family cytokines in TBL.

Women Serum Concentrations of the IL-10 Family of Cytokines and IFN-γ Decrease from the Third Trimester of Pregnancy to Active Labor.

Labor is regarded as increased myometrial activity with a regular contractility pattern. At this final stage of pregnancy, myometrial quiescence is lost, accompanied by altered immune homeostasis. It is well known that the interleukin (IL)-10 family of cytokines modulates immunological responses mainly in epithelial cells, including the endometrium. To investigate their inflammatory profile during labor, we performed a longitudinal study in a group of healthy pregnant women (n = 20) with uncomplicated pregnancies in the third trimester of pregnancy and during active labor. Blood was sampled from pregnant women in the third trimester (gestational age 32-38 weeks, mean 36 ± 2 weeks) and during active labor (39-41 weeks of gestation, mean 40 ± 1 weeks). Serum levels of several cytokines were measured using multiplex immunoassays for both stages, indicating that the concentrations of IL-10, IL-20, IL-22, IL-28A, and interferon (IFN)-γ were significantly decreased during active labor in comparison with third-trimester levels (p < 0.05). Our analysis did not find significant correlations between IL-10, IL-20, IL-22, IL-28A, and IFN-γ levels and gestational age. However, our data suggest that the systemic downregulation of several members of the IL-10 family of cytokines plays an important role in the activation of myometrial smooth cells associated with uterine contractions during active labor. Downregulation of this IL-10 family of cytokines seems to coincide with the well-reported functional progesterone withdrawal during labor. Likewise, lower plasma IFN-γ concentrations may indicate a role for IFN-γ in active labor.

Distribution of interleukin-10 family cytokines in serum and synovial fluid of patients with inflammatory arthritis reveals different contribution to systemic and joint inflammation.

Evidence exists that interleukin (IL)-10 family cytokines may be involved in the pathogenesis of rheumatoid arthritis (RA). We sought to determine whether or not these cytokines are involved in psoriatic arthritis (PsA). We conducted a prospective study on patients with PsA, RA and osteoarthritis (OA); healthy controls (HC) were also included. We analysed IL-20, IL-24 and IL-19 serum and synovial fluid (SF) levels and change of serum levels following treatment with biological agents. IL-20 serum levels were increased in PsA and RA compared with OA patients and HC and with matched SF levels. IL-24 serum levels in PsA, RA and OA patients were higher than those in HC and also with respect to matched SF in PsA. IL-19 serum levels were higher in HC and OA compared with PsA and RA patients; IL-19 SF levels were higher in PsA and RA compared with OA patients, and in PsA compared with RA patients. PsA and RA patients showed a reduction of IL-19 serum levels after biological treatment. Therefore, IL-19 seems to be involved mainly in the joint inflammation, whereas IL-20 and IL-24 appear to participate mainly in the systemic responses. These findings may further the comprehension of the contribution of these cytokines to the inflammatory response involved in chronic arthritis, as well as to the development of novel therapeutic strategies.