Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

Abstract

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

Chlorin e6-Induced Photodynamic Effect Polarizes the Macrophage Into an M1 Phenotype Through Oxidative DNA Damage and Activation of STING

“…Apart from the driving factor of oxidative damage, the STING and its downstream NF-κB are key molecules that mediate the pro-inflammatory response of macrophages ( Hou et al, 2018 ; Dunphy et al, 2018 ; Sun et al, 2020 ). The inflammatory response wherein macrophages is one of the essential contributors to their remodeling to the M1 phenotype ( Lin et al, 2020 ). In light of Ce6 PDT’s effect on the STING and subsequent NF-κB, we proceeded to investigate the role of the STING molecule in the PDT-mediated reprogramming of macrophages to establish a logical link between them thereupon.…”

“…The activation of NF-κB promotes the inflammatory response of macrophages on the one hand, thereby effectively changing them from a pro-tumor M2 phenotype to a pro-inflammatory, anti-tumor M1 phenotype. NF-κB is also a nuclear transcription factor that boosts the expression of a series of proteins such as iNOS and GBP5 ( Lin et al, 2020 ). These indicated that the STING molecule was centrally located in the PDT-mediated macrophage reprogramming process.…”

Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications

“…FLSs and macrophages produce IL-26 and IL-29, respectively. IL-26 can promote the polarization of M1 macrophages by activating the c-JUN/NF-kB/STAT1 signaling pathway and produce IL-6 and TNF-a pro-inflammatory factors (177). IL-29 is elevated in the serum of RA patients and participates in the chemotaxis of peripheral blood neutrophils, inhibits T follicular helper (Tfh) cell differentiation by reducing STAT3/BCL6 activity, and induces RANKL expression in FLSs through the MAPK pathway to participate in bone destruction.…”

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

“…It is worth mentioning that IL-20R1 is restricted to epithelial cells and some myeloid cells, but IL-10R2 is ubiquitously expressed [13,14]. Although it has not been found any IL-26 orthologs in rodents, several murine cells have been confirmed to express the receptor for IL-26 and respond to its administration [15][16][17]. Upon IL-26 interaction with its receptor complex, it induces Janus kinase (JAK)1 and tyrosine kinase (TyK)2 signalling, which lead to phosphorylation and activation of signal transducer and activator of transcription (STAT)1 and STAT3 [11,12].…”

“…IL-26 administration to monocyte cells activates NF-κB and cJUN transcription factors and differentiates these cells into STAT1-expressing CD80 + /CD86 + M1 macrophages that can produce IL-6 and TNF-α. In addition, the treatment of bone marrow-derived monocytes with IL-26 also skewed these cells towards the CD206 + / CD80 + M1 phenotype [17]. Other than immune response skewness in favour of RA, it has also been shown that IL-26 affects osteoclasts and promotes osteoclastogenesis.…”