Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells.

The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific Furin gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of Furin gene was identified. When this region was deleted with CRISPR/Cas9 the production of Furin mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel Furin regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally, Furin genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of Furin expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.

Chronically reduced IL-10 plasma levels are associated with hippocampal sclerosis in temporal lobe epilepsy patients.

BACKGROUND: Increasing evidence supports the role of soluble inflammatory mediators in the pathogenesis of refractory temporal lobe epilepsy (TLE). Hippocampal sclerosis (HS) is a well-described pathohistological abnormality in TLE. The association of proinflammatory cytokines with epileptic disease profiles is well established; however, the potential significance of circulating interleukin 10 (IL-10), particularly in TLE-associated HS, is still poorly understood. Therefore, taking into consideration the neuroprotective and anticonvulsive effects of IL-10, we performed this study to examine the role of the plasma levels of IL-10 in patients with TLE with HS (TLE + HS), TLE without HS (TLE-HS) and with other types of epilepsy. METHODS: This study included 270 patients with refractory epilepsy who were classified into four groups: i) 34 patients with TLE + HS, ii) 105 patients with TLE-HS, iii) 95 patients with extra-TLE (XLE) and iv) 36 patients with idiopathic generalized epilepsy (IGE). The plasma IL-10 levels were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-10 levels were significantly lower in TLE + HS than in TLE-HS (p = 0.013). In a subgroup of TLE-HS patients who had seizures 1 month before sampling, patients with seizures had significantly higher IL-10 levels than patients who were seizure-free (p = 0.039). Among a small group (n = 15) of non-refractory TLE-HS patients, IL-10 levels showed a moderate negative correlation with the duration of epilepsy (r = - 0.585, p = 0.023). CONCLUSIONS: This study demonstrated that chronically reduced levels of plasma IL-10 were associated with HS in TLE patients, suggesting that there was an inadequate systemic anti-inflammatory immune response. These results could provide new biological insights into the pathophysiology of HS in TLE. We also found that the production of IL-10 could be affected by the seizure frequency and declined concomitantly with increased disease durations. Therefore, the measurement of plasma IL-10 may have diagnostic value as a biomarker for stratifying TLE + HS from other epilepsy types or as a marker of disease progression towards a progressive form of epilepsy.

Proprotein convertase enzyme FURIN is upregulated in primary Sjögren's syndrome.

OBJECTIVES: The proprotein convertase enzyme FURIN is a critical regulator of the anti-inflammatory TGFß-1 cytokine and peripheral immune tolerance. In T cells, FURIN is co-regulated with IFN-γ and thus highly expressed in T helper 1 type cells. Previous studies have demonstrated that FURIN is upregulated in inflammatory conditions, including atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus. Here, we evaluated the levels of FURIN in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) and in healthy controls. METHODS: FURIN plasma levels were determined by ELISA, and the mRNA expression in PBMCs was quantitated using qPCR. FURIN levels in the plasma were correlated with the clinical and demographic characteristics of the patients. RESULTS: FURIN was found to be significantly upregulated at both the protein and mRNA level in pSS patients compared to healthy controls. In pSS patients, high FURIN protein levels were significantly associated with elevated IFN-γ levels in the plasma as well as a longer duration of sicca symptoms in the eyes. pSS patients with high FURIN levels in their plasma showed a trend towards lower levels of serum beta-2 microglobulin, ESR and a lower systemic disease activity index ESSDAI. CONCLUSIONS: The proprotein convertase FURIN is significantly upregulated in pSS. Elevated FURIN levels associate with high levels of the Th1 type cytokine IFN-γ and long duration of dry eye symptoms. Patients with high FURIN levels show signs of lower disease activity suggesting that FURIN might have a protective role in pSS.

Myeloid cell expressed proprotein convertase FURIN attenuates inflammation.

The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1ß levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-ß1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.

[Innate lymphoid cells - a new group of immune cells]. / Luontaiset Iymfosyytit - uusi immuunisoluryhmä.

A new group of immune cells, innate lymphoid cells, i.e. ILC cells has recently been identified in the territory between the cells of innate and acquired immunity. While the understanding of their functioning and grouping still remains incomplete, their importance in defending the interfaces of the body seems clear. The central role of ILC cells is to sense danger signals in the body and modify immune responses on the basis of this information. In addition to understanding of the defense response, future research. on ILC cells is expected to provide information about the mechanisms of autoimmunity and allergic inflammation as well as disorders of immunity associated with cancer and obesity.