The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis

Xu, Dan; Mu, Rong; Wei, Xiaofan

doi:10.3389/fimmu.2019.02025

Cited by 79 publications

(65 citation statements)

References 67 publications

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“…SSc is a chronic and multisystem AID with major characteristic skin and organ fibrosis as the result of vasculopathy, action of autoantibodies, and deposition of excessive collagen [13]. Both innate and adaptive immune systems have been shown to contribute to the pathogenesis of SSc; cytokines such as IL-1α, IL-1β [25], IL-18, IL-13, and IL-4 [26] produced by various immune cells have pro-inflammatory and pro-fibrotic effects. We report here that levels of IL-38 were significantly higher in new untreated patients than in treated patients and also than in healthy control subjects.…”

Section: Discussionmentioning

confidence: 99%

Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients

et al. 2020

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Objective: Interleukin (IL)-38 is a newly discovered member of the IL-1 cytokine family with a proposed anti-inflammatory profile. We studied the probable role of this cytokine in the pathogenesis of two autoimmune diseases: multiple sclerosis (MS) and systemic sclerosis (SSc). Subjects and Methods: A total of 87 MS patients and 86 SSc patients (40 new and recently untreated cases and 46 treated cases) were selected for this study. Eighty-seven and 80 age- and sex-matched healthy subjects were included as controls for MS and SSc, respectively. Clinical and paraclinical features of the patients were recorded at the time of sampling. Serum IL-38 was measured by ELISA. Results: Levels of serum IL-38 did not significantly differ between the total MS or SSc patients compared to controls. However, levels of IL-38 were significantly higher in newly diagnosed patients of MS (206.43 ± 38.97 pg/mL, p < 0.0001) than in those previously treated (158.04 ± 39.45 pg/mL). Similarly, new/recently untreated cases of SSc patients showed increased IL-38 levels (185.19 ± 36.27 pg/mL, p = 0.001) compared to treated patients (166.82 ± 33.08 pg/mL). IL-38 levels in newly diagnosed MS patients (p = 0.007) and new/recently untreated SSc patients (p = 0.032) were significantly higher than those in healthy controls. Conclusion: The higher serum levels of IL-38 in new or recently untreated cases of MS and SSc patients than in treated patients and healthy controls suggest the possible role of this cytokine in the development of these diseases or as part of a feedback loop to attenuate the inflammatory conditions in early stages of these diseases.

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Section: Discussionmentioning

confidence: 99%

Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients

et al. 2020

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“…SSc is an idiopathic autoimmune syndrome that exhibits fibrosis in the skin and other organs like the heart and lungs, due to fibroblast activation and deposition of extracellular matrix (262). IL-1a and IL-1b regulate IL-6 and PDGF-A expression on SSc fibroblasts, promoting collagen deposition and proliferation (263,264) and differentiation into myofibroblasts (265)(266)(267).…”

Section: Il-1 Regulates Fibroblast Differentiation In Systemic Sclerosismentioning

confidence: 99%

Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease

2020

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Cytokines activate or inhibit immune cell behavior and are thus integral to all immune responses. IL-1α and IL-1β are powerful apical cytokines that instigate multiple downstream processes to affect both innate and adaptive immunity. Multiple studies show that IL-1β is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing of IL-1β and its release. However, many alternative mechanisms activate IL-1α and IL-1β in atypical cell types, and IL-1 function is also important for homeostatic processes that maintain a physiological state. This review focuses on the less studied, yet arguably more interesting biology of IL-1. We detail the production by, and effects of IL-1 on specific innate and adaptive immune cells, report how IL-1 is required for barrier function at multiple sites, and discuss how perturbation of IL-1 pathways can drive disease. Thus, although IL-1 is primarily studied for driving inflammation after release from macrophages, it is clear that it has a multifaceted role that extends far beyond this, with various unconventional effects of IL-1 vital for health. However, much is still unknown, and a detailed understanding of cell-type and context-dependent actions of IL-1 is required to truly understand this enigmatic cytokine, and safely deploy therapeutics for the betterment of human health.

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“…Immunohistochemical studies indicated that intracellular IL-1a is also markedly expressed in fibroblasts isolated from skin lesions of SSc patients; in addition, endogenous IL-1a induces fibroblast proliferation and production of collagen by inducing IL-6 and platelet-derived growth factor (PDGF) (36). Consistently, the production of IL-6, suppression of IL-1a through IL-1a siRNA results in decreased PDGF and procollagen production in SSc-affected fibroblasts (37), whereas overexpression of IL-1a through transfection in healthy fibroblasts promotes differentiation into a SSc-related phenotype (34). In SSc fibroblasts, the NLRP3 inflammasome is over-expressed and caspase-1 activity is up-regulated with consequent increased production of IL-1b and IL-18, whereas inhibition caspase-1 and inflammasome activity abrogated the myofibroblast phenotype in SSc dermal and lung fibroblasts (38)(39)(40).…”

Section: Il-1 and The Inflammasome In Sscmentioning

confidence: 91%

Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

et al. 2021

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Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called “vascular hypothesis” represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an “inflammation-driven pathway to fibrosis”. The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

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The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis

Cited by 79 publications

References 67 publications

Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients

Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients

Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease

Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

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