The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms

Li, Yanxia; Zhao, Jing; Yuan, Yin; Li, Ké; Zhang, Chenchen; Zheng, Y.

doi:10.7150/ijbs.75876

Cited by 50 publications

(32 citation statements)

References 89 publications

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“…In the PBMCs activation assay, YG-003D3 induced stronger IFN-g, IL-6, and TNF-a secretion compared to that induced by its parental anti-PD-1 or anti-LAG-3 antibodies. Although IL-6 is not the major cytokine secreted by T cells, some literature reports that IL-6 may be secreted by monocytes, macrophages, and dendritic cells (62)(63)(64). Therefore, it can be speculated that YG-003D3 may affect other immune cells, either directly or indirectly, and then induce the expression of IL-6.…”

Section: Discussionmentioning

confidence: 99%

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy

Shi

Zhou

Liu³

et al. 2022

Front. Immunol.

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Several clinical studies demonstrate that there exist other immune checkpoints overexpressed in some PD-1 inhibitor-resistant tumor patients. Among them, Lymphocyte-activation gene 3 (LAG-3) is one of the important immune checkpoint molecules and has been clinically demonstrated to have synergistic anti-tumor effects in combination with PD-1 antibody. In this study, we designed a novel ‘knob-in-hole’ PD-1/LAG-3 bispecific antibody (BsAb) YG-003D3. In conclusion, the BsAb maintained the similar affinity and thermal stability to the parental antibody, and the BsAb structure can be independent of each other in the process of double-target recognition, and the recognition activity will not be affected. Moreover, the BsAb can not only target PD-1 and LAG-3 on single cell simultaneously, but also bridge the two kinds of cells expressing PD-1 and LAG-3, so as to release the ‘brake system of immune checkpoints’ and activate immune cells to exert anti-tumor effects more effectively. Especially in the PBMCs activation assay, YG-003D3 induced stronger IFN-γ, IL-6, and TNF-α secretion compared to anti-PD-1 or anti-LAG-3 single drug group or even combined drug group. In the tumor killing experiment of PBMC in vitro, YG-003D3 has a better ability to activate PBMC to kill tumor cells than anti-PD-1 or anti-LAG-3 single drug group or even combined drug group, and the killing rate is as high as 20%. In a humanized PD-1/LAG-3 transgenic mouse subcutaneous tumor-bearing model, YG-003D3 showed good anti-tumor activity, even better than that of the combination group at the same molar concentration. Further studies have shown that YG-003D3 could significantly alter the proportion of immune cells in the tumor microenvironment. In particular, the proportion of CD45+, CD3+ T, CD8+ T cells in tumor tissue and the proportion of CD3+ T, CD8+ T, CD4+ T cells in peripheral blood were significantly increased. These results suggest that YG-003D3 exerts a potent antitumor effect by activating the body ‘s immune system. In summary, the BsAb YG-003D3 has good anti-tumor activity, which is expected to become a novel drug candidate for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy

Shi

Zhou

Liu³

et al. 2022

Front. Immunol.

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“…The Immuno‐related procedures used comply with the recommendations made by the British Journal of Pharmacology (Alexander et al, 2018). IL‐6 was measured as it is strongly associated with the onset of fibrosis (Li et al, 2022). Culture medium and perfusate samples were analysed with a Porcine IL‐6 Duo Set enzyme‐linked immunosorbent assay (ELISA) (Bio‐Techne, Abingdon, UK), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

van Leeuwen,

Ruigrok,

Kessler

et al. 2023

British J Pharmacology

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Background and purposeFibrosis in kidney allografts is a major post‐transplant complication that contributes to graft failure. Lately, multiple potent inhibitors of fibrosis‐related pathways have been developed such as galunisertib—an inhibitor of the transforming growth factor‐beta (TGF‐β) signaling pathway. This drug, however, poses risks for adverse effects when administered systemically. Therefore, we devised a new repurposing strategy in which galunisertib is administered ex vivo. We combined machine perfusion and tissue slices to explore the antifibrotic effects of galunisertib in renal grafts.Experimental approachPorcine kidneys were subjected to 30 min of warm ischemia, 24 h of oxygenated hypothermic machine perfusion, and 6 h of normothermic machine perfusion with various treatments (i.e., untreated control, TFG‐β, galunisertib, or TGF‐β+galunisertib; n=8 kidneys per group). To determine whether effects persisted upon ceasing treatment, kidney slices were prepared from respective kidneys and incubated for 48 h.Key resultsGalunisertib treatment improved general viability without negatively affecting renal function or elevating levels of injury markers or byproducts of oxidative stress during perfusion. Galunisertib also reduced inflammation and more importantly, reduced the onset of fibrosis after 48 h incubation.Conclusions and implicationsOur findings demonstrate the value of using machine perfusion for administering anti‐ fibrotic drugs, such as galunisertib, proving it to be an effective example of repurposing.

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“…Bou‐Gragham's study showed that overexpression of IL‐1α was associated with the worsening of symptoms and disease progression in conditions such as atopic dermatitis, neutrophilic dermatoses, skin phototoxicity, and skin cancer 4 . Similarly, IL‐6 was found to activate TGF‐β, NF‐κB, STAT3, and ERK pathways, while also triggering oxidative stress through the production of reactive oxygen species 5 . In Khan's research, the elevated IL‐6 level was found to correlate with the severity of skin manifestations and the degree of skin thickening, both of which contribute to skin fibrosis—a characteristic feature of systemic sclerosis 6 .…”

Section: Introductionmentioning

confidence: 99%

Glutamic‐acid grafted hyaluronic acid inhibits inflammatory factors via fibroblast and skin model tests

Jiang,

Wang,

Han

et al. 2024

Skin Research and Technology

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BackgroundExcessive inflammation may cause tissue damage and disrupt the function of the skin barrier. Hyaluronic acid (HA), an endogenous component, was found to regulate multiple inflammatory factors for skin health. This work aims to further enhance its efficacy by grafting amino acid onto its molecule.MethodsGlutamic acid (Glu) was selected as the ligand to react with low‐molecular‐weight HA. Fibroblast tests and a 3D skin model were used to investigate the anti‐inflammation efficacy of HA‐Glu.ResultsFor IL‐1α, IL‐6 and TNF‐α, the grafted compound presents stronger inhibition ability versus native HA. Moreover, HA‐Glu could promote the repair of damaged skin by improving the compactness of the stratum corneum and increasing the thickness of the living cell layer.ConclusionThe application of HA‐Glu compound in skin care formulas would be effective to alleviate inflammation‐induced skin symptoms and skin aging.

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The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms

Cited by 50 publications

References 89 publications

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy

Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

Glutamic‐acid grafted hyaluronic acid inhibits inflammatory factors via fibroblast and skin model tests

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