Journal of Interferon & Cytokine Research

IFN-γ is recognized as an immunoregulatory cytokine due to its dual role in both accelerating and dampening immunological responses. Accordingly, in the context of tumor immunotherapy, the therapeutic outcome of IFN-γ is contingent upon factors such as dosage and the expression status of downstream signaling molecules. Furthermore, the coadministration of IFN-γ with various immunestimulatory agents, including anticheckpoint inhibitors, chemotherapeutic agents, and herbal-based medicines, may potentially overcome the IFN-γ-related challenges and enhance the response rate. We decipher the mechanisms of tumor cell eradication facilitated by IFN-γ, the last achievements in IFN-γ-mediated tumor immunotherapy across various cancers, and the strategies to address the failure of IFN-γ-based tumor immunotherapy. Unraveling the molecular mechanisms that lead to failure in IFN-γ-based antitumor actions could assist in pinpointing therapeutic agents that target the immune-modulatory features of IFN-γ, thereby increasing the antitumor response rate.

Distinct transcriptional isoforms of the interferon lambda receptor 1 (IFNLR1) are expressed in hepatocytes, but whether corresponding full-length and truncated IFNLR1 protein variants have discrete function is unclear. We quantitated IFNLR1 isoforms in liver and blood from individuals with chronic hepatitis C virus (HCV) infection before and after antiviral treatment, hypothesizing their relative expression may differentially change during resolution of virus-induced inflammation. We also expressed FLAG-tagged IFNLR1 variants in stem cell-derived hepatocytes (iHeps) with abrogated endogenous IFNLR1 to evaluate their function. IFNLR1 isoforms decreased in liver and blood during treatment of HCV, but no distinct pattern of decline was observed for any individual isoform. Expression of full-length IFNLR1 enabled lambda interferon (IFNL)-induced expression of antiviral and proinflammatory genes and augmented inhibition of hepatitis B virus (HBV) replication relative to wild-type (WT) iHeps. A noncanonical IFNLR1 variant missing part of the JAK1 binding domain enabled IFNLs to induce antiviral genes but could not support induction of proinflammatory genes or augmented HBV inhibition beyond that observed in WT iHeps with intact endogenous IFNLR1. A secreted IFNLR1 variant had no identified function in iHeps lacking endogenous IFNLR1. Although relative expression of individual IFNLR1 isoforms did not distinctly change during HCV treatment, functional studies in iHeps suggest IFNLR1 variants could function to titrate antiviral versus proinflammatory responses in hepatocytes in the context of viral hepatitis.

Respecting the significant role of inflammation in acute ischemic stroke (AIS) development, we explored the correlations of inflammatory cytokines and lipoprotein-associated phospholipase-A₂ (Lp-PLA₂) with AIS and their early prognostic value. The retrospectively enrolled subjects [Study (AIS patients) and Control (healthy volunteers) groups] were determined for serum index levels. Neurological impairment and early prognosis of AIS patients were assessed. The relationship of National Institutes of Health Stroke Scale (NIHSS) and the indexes and the risk factors and predictive value of peripheral blood inflammatory cytokines combined with Lp-PLA₂ for poor early prognosis were analyzed. Interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and Lp-PLA₂ levels rose in AIS patients, while IL-10 dropped. The NIHSS score positively correlated with IL-1β, TNF-α, and Lp-PLA₂ and negatively correlated with IL-10. As AIS aggravated, IL-1β, IL-6, TNF-α, and Lp-PLA₂ rose dependently, but IL-10 dropped. Patients in the poor early prognosis group had higher diabetes proportions, NIHSS scores and serum IL-1β, IL-6, TNF-α, and Lp-PLA₂ levels at admission, as well as lower IL-10 levels than those in the good early prognosis group. IL-6, IL-1β, TNF-α, and Lp-PLA₂ were risk factors, but IL-10 was a protective factor against poor early prognosis in AIS patients, with their combined detection showing high predictive value. Collectively, highly expressed IL-6, TNF-α, IL-1β, and Lp-PLA₂ and lowly expressed IL-10 in patients with AIS closely related to AIS development and early prognosis, and their combination could increase the predictive value of NIHSS for AIS poor early prognosis.

Cytokines are crucial in controlling inflammation during viral infection, particularly infection with the hepatitis C virus (HCV). Cytokine genetic polymorphisms can change how the immune system responds to this infection. We investigated how the HCV infection treatment was affected by single nucleotide polymorphisms in these genes. The goal of this study was to examine any connections between the cytokine gene polymorphisms for interleukins (IL)-22-binding protein rs6570136, as well as IL-10 rs1800872 and rs1878672 in the Pakistani population and responsiveness to direct-acting antivirals (DAAs) treatment. This study evaluated 155 participants, which included 55 patients who achieved sustained virologic response (SVR), 40 relapse patients, and 60 healthy controls, to assess and compare the clinical parameters. The SVR and relapse groups were compared for their allelic and genotypic frequencies. We discovered that the SVR and the relapse groups had significantly different genotype frequencies for IL-10 rs1800872 and IL-22BP rs6570136 in the Pakistani population. The G/G genotype in rs6570136 and A/A genotype in rs1800872 were significantly associated with relapse following DAA therapy, with P values 0.002 and 0.0004, respectively. In contrast, rs1878672 showed no significant correlation with HCV relapse, P = 0.63.