Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signaling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials.
We ...performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (<85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19.
From May 2020–March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66–1∙88; p >0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients).
In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19.
Janssen Research & Development, LLC
•Adults with severe or critical COVID-19 were randomised to sirukumab or placebo Sequestration of IL-6 upstream of the IL-6R allows testing of the IL-6 hypothesis•Sirukumab sequestered circulating IL-6 available for cis and trans signaling•Time to sustained clinical improvement was not significantly different by group•24.6% vs 30.0% of critically ill patients died with sirukumab vs placebo
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 ...(IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.
Interleukin-6 (IL-6) is a pleiotropic cytokine with effects in immune regulation, inflammation, and infection. The use of drugs that inhibit IL-6 biological activity has been proposed as a treatment ...for patients with Coronavirus Disease 2019 (COVID-19). The rationale for this approach includes commitment to the concept that inflammation is a cause of lung damage in COVID-19 and belief that IL-6 is a pro-inflammatory molecule. Observational data thought to support IL-6 inhibition include elevated circulating IL-6 levels in COVID-19 patients and association between elevated IL-6 and poor clinical outcomes. However, IL-6 has significant anti-inflammatory properties, which calls into question the rationale for employing IL-6 blockade to suppress inflammation-induced tissue injury. Also, studies suggesting a beneficial role for IL-6 in the host response to infection challenge the strategy of using IL-6 blockade to treat COVID-19. In studies of recombinant IL-6 injected into human volunteers, IL-6 levels exceeding those measured in COVID-19 patients have been observed with no pulmonary adverse events or other organ damage. These observations question the role of IL-6 as a contributing factor in COVID-19. Clinical experience with IL-6 receptor antagonists such as tocilizumab demonstrates increase in severe and opportunistic infections, raising concern about using tocilizumab and similar agents to treat COVID-19. Trials of drugs to inhibit IL-6 activity in COVID-19 are ongoing and will shed light on the role of IL-6 in COVID-19 pathogenesis. However, until more information is available, providers should exercise caution in prescribing these therapies given the potential for patient harm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor ...antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6−/− mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6Chigh monocytes and neutrophils were increased in the colon of Il6−/− mice. Intestinal crypts more strongly increased the migration of Il6−/− macrophages than wild-type ones. Moreover, Il6−/− macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6−/− mice. Collectively, these results indicate that Il6−/− macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6−/− on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.
A proposed model illustrating the mechanism of IL-6 deficiency promoting DSS-induced colitis. IL-6 deficiency aggravates DSS-induced colitis by recruiting circulating Ly6Chi monocytes in a CCL2-CCR2-dependent manner to colon tissues. Furthermore, under inflammation conditions, Il6−/− macrophages promote the migration of neutrophils to the colon tissues by secreting neutrophils chemokines, such as CXCL1, CXCL2, and IL-23. The overactivated neutrophils form NETs, which secrete anti-microbial molecules such as MPO. MPO damages intestinal epithelium and aggravates the development of colitis. Display omitted
•IL-6 physiological deficiency facilitates the development of DSS-induced colitis.•IL-6 deficiency promotes colitis by recruiting Ly6Chi monocytes into inflamed colon tissue CCR2 antagonist blocks the chemotaxis of macrophages and terminate the aggravating colitis in in a CCL2-CCR2-dependent manner.•IL-6-deficient macrophages recruit more neutrophils which secreted MPO, destroy the intestinal epithelium.•This study enlightens our knowledge on the pathology of gastrointestinal immune adverse effects of IL-6 antagonists.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, ...but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.
Therapeutic strategies targeting the IL-6 axis are being used to treat various autoimmune and inflammatory diseases. Kishimoto and colleagues review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Interleukin-6 (IL-6) is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects hematopoiesis, metabolism, and organ development. IL-6 can simultaneously ...elicit distinct or even contradictory physiopathological processes, which is likely discriminated by the cascades of signaling pathway, termed classic and trans-signaling. Besides playing several important physiological roles, dysregulated IL-6 has been demonstrated to underlie a number of autoimmune and inflammatory diseases, metabolic abnormalities, and malignancies. This review provides an overview of basic concept of IL-6 signaling pathway as well as the interplay between IL-6 and renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Additionally, we summarize the roles of IL-6 in several renal diseases, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, acute kidney injury, and chronic kidney disease.
COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in ...pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called "cytokine storm" induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.
Interleukin-6 (IL-6) enhanced TNF-α and TRAIL/Apo2L induced cell death in various human cancer cells derived from malignant glioma, melanoma, breast cancer and leukemia, although the effect was not ...detected with IL-6 alone. The effects of IL-6 using SKBR3 cells were associated with the generation of apoptotic cells as analyzed by fluorescence microscopy and flow cytometry. IL-6 activated p53 and upregulated TRAIL death receptors (DR-4 and DR-5) and stimulated the TNF-α and TRAIL dependent extrinsic apoptotic pathway without activation of the p53 mediated intrinsic apoptotic pathway. TNF-α and TRAIL induced cleavage of caspase-8 and caspase-3 was more enhanced by IL-6, although these caspases were not cleaved by IL-6 alone. The dead cell generation elicited by the combination with IL-6 was blocked by anti-human TRAIL R2/TNFRSF10B Fc chimera antibody which can neutralize the DR-5 mediated death signal. These findings indicate that IL-6 could contribute to the enhancement of TNF-α or TRAIL induced apoptosis through p53 dependent upregulation of DR-4 and DR-5. The data suggest that a favorable therapeutic interaction could occur between TNF-α or TRAIL and IL-6, and provide an experimental basis for rational clinical treatments in various cancers.
•IL-6 enhanced TNF-α and TRAIL/Apo2L induced cell death in human cancer cells.•IL-6 promotes cell death through p53 dependent upregulation of death receptors.•IL-6 sensitizes fas and TRAIL mediated extrinsic apoptotic pathway.•IL-6 enhanced the cleavage of caspase-8 and caspase-9 promoted by TNF-α and TRAIL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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