The enigmatic role of IL-38 in inflammatory diseases

Garraud, Thomas; Harel, Mathilde; Boutet, Marie-Astrid; Goff, Benoît Le; Blanchard, Frédéric

doi:10.1016/j.cytogfr.2018.01.001

Cited by 56 publications

(72 citation statements)

References 92 publications

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“…31,32 However, IL-38 does not appear to affect intrinsic antibacterial activity of phagocytes. 31,32 However, IL-38 does not appear to affect intrinsic antibacterial activity of phagocytes.…”

Section: Discussionmentioning

confidence: 97%

“…[31][32][33] There is growing interest in investigating the regulatory pathway of IL-38 in the pathogenesis of inflammatory and autoimmune disorders. (A, B) Flow cytometry plots showed CD4 + CD25 + Tregs in the spleen at 48 h after treatment with anti-CD25 antibody (PC61) (n = 6 per group).…”

Section: Discussionmentioning

confidence: 99%

“…***P < .001 vs mice treated with IgG1 as a control bacteria, Toll-like receptor (TLR) agonists or other pathogens, although IL-38 expression in CD4 + CD25 + Tregs has been unclear. [31][32][33] There is growing interest in investigating the regulatory pathway of IL-38 in the pathogenesis of inflammatory and autoimmune disorders. High concentrations of IL-38 have been observed in patients with asthma, chronic hepatitis B, rheumatic arthritis and Crohn's disease, and its expression is associated with the severity of these diseases.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells

Huang

et al. 2019

J Cellular Molecular Medi

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| INTRODUC TI ONCD4 + CD25 + regulatory T cells (Tregs) can regulate host responses to infections and tumours, and contribute to the prevention of allergies, autoimmune diseases and transplant rejection. 1-4 CD4 + CD25 + Tregs are essential for maintenance of immune homeostasis and self-tolerance. They express several crucial molecular markers, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also termed CD152), glucocorticoid-induced tumour necrosis factor receptor (GITR) and forkhead/winged helix transcription factor p3 (Foxp3).Knockdown of these factors leads to lethal lymphoproliferative phenotypes. 5-8 Concomitantly, CD4 + CD25 + Tregs can produce various potent anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor (TGF)-β, which cause immunosuppression of effector T cells. 9-12 Moreover, CD4 + CD25 + Tregs can reduce IL-2 production and inhibit polyclonal T cell activity in vitro, 13 and Abstract Naturally occurring CD4 + CD25 + regulatory T cells (Tregs) are required to limit immune-induced pathology and to maintain homeostasis during the early-phase of sepsis. This study aimed to investigate the role of interleukin (IL)-38, a newly described member of the IL-1 cytokine family, in mediated immune response of CD4 + CD25 + Tregs in sepsis. Here, we provide evidence that expressions of IL-38 and its receptor were detected in murine CD4 + CD25 + Tregs. Stimulation of CD4 + CD25 + Tregs with LPS markedly up-regulated the expression of IL-38. Treatment with rmIL-38 dramatically enhanced the immunosuppressive activity of CD4 + CD25 + Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti-IL-38 antibody was administered. Administration of rmIL-38 improved the survival rate of CLP mice. In addition, CD4 + CD25 + Tregs depletion before the onset of sepsis obviously abolished IL-38-mediated protective response. These findings suggest that IL-38 enhances the immunosuppressive activity of CD4 + CD25 + Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis. K E Y W O R D Simmune response, interleukin-38, regulatory T cells, sepsis

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells

Huang

et al. 2019

J Cellular Molecular Medi

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“…IL‐38 is able to block IL‐36–driven IL‐23/IL‐17 axis and has been implicated in numerous arthritis models . SNP in IL‐38 has been associated with AS patients . PGE2 is also viewed as a potential IL‐23 inducer in health and disease .…”

Section: Animal Models Showing a Role For Il‐23 In Enthesitismentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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“…IL‐1α, IL‐1β, IL‐18, IL‐33, IL‐36α, IL‐36β and IL‐36γ are pro‐inflammatory signalling molecules of this family. Structurally similar IL‐1 family members of the opposite biological effect, that is suppression of inflammation, are IL‐1 receptor antagonist (RN), IL‐36RN, IL‐37 and IL‐38 . IL‐1 family cytokines are differentially expressed in epidermal keratinocytes, and, remarkably, IL‐36β, IL‐36γ, IL‐36RN, IL‐37 and IL‐38 are expressed in keratinocytes at higher levels than in any other cell type …”

Section: Cell Death Is a Major Trigger Of Inflammation Unless Alarm Smentioning

confidence: 99%

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

Eckhart

Tschachler

2018

Experimental Dermatology

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The function of the skin as a barrier to the environment is mainly achieved by the outermost layers of the epidermis. In the granular layer, epidermal keratinocytes undergo the last steps of their terminal differentiation program resulting in cornification. The coordinated conversion of living keratinocytes into corneocytes, the building blocks of the cornified layer, represents a unique form of programmed cell death. Recent studies have identified numerous genes that are specifically expressed in terminally differentiated keratinocytes and, surprisingly, this genetic program does not only include mediators of cornification but also suppressors of pyroptosis, another mode of programmed cell death. Pyroptosis is activated by inflammasomes, leads to the release of interleukin-1 (IL-1) family cytokines, and thereby activates inflammation. In addition, inhibitors of potentially pro-inflammatory proteases and enzymes removing danger-associated cytoplasmic DNA are expressed in differentiated keratinocytes. We propose the concept of cornification as an inherently hazardous process in which damaging side effects are actively suppressed by protective mechanisms. In support of this hypothesis, loss-of-function mutations in epidermal protease inhibitors and IL-1 family antagonists suffice to induce autoinflammation. Similarly, exogenous disturbances of either cornification or its accompanying control mechanisms may be starting points for skin inflammation. Further studies into the relationship between cornification, pyroptosis and other forms of cell death will help to define the initiation phase of inflammatory skin diseases and offer new targets for disease prevention and therapy.

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The enigmatic role of IL-38 in inflammatory diseases

Cited by 56 publications

References 92 publications

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

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The enigmatic role of IL-38 in inflammatory diseases

Cited by 56 publications

References 92 publications

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4+CD25+ regulatory T cells

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4+CD25+ regulatory T cells

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

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Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4⁺CD25⁺ regulatory T cells