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IFN? is a potent anti-influenza therapeutic without the inflammatory side effects of IFN? treatment.

ABSTRACT: Influenza A virus (IAV)-induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFN??) and type III interferon (IFN?) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFN? treatment of IAV-infected Mx1-positive mice lowered viral load and protected from disease. IFN? treatment also restricted IAV replication but exacerbated disease. IFN? treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFN?-treatment. IFN? lacked the direct stimulatory activity of IFN? on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFN? and IFN? by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFN?. The restriction of both IFN? responsiveness and productive IAV replication to pulmonary epithelia allows IFN? to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFN? as a non-inflammatory and hence superior treatment option for human IAV infection.

SUBMITTER: Davidson S

PROVIDER: S-EPMC5009813 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment.

Davidson Sophia S McCabe Teresa M TM Crotta Stefania S Gad Hans Henrik HH Hessel Edith M EM Beinke Soren S Hartmann Rune R Wack Andreas A

EMBO molecular medicine 20160901 9

Influenza A virus (IAV)-induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFNαβ) and type III interferon (IFNλ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFNλ treatment of IAV-infected Mx1-positive mice lowered viral load and protected from disease. IFNα treatment also restricted IAV replication but exacerbated disease. IFNα treatment ...[more]

PMID: 27520969

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Project description:Marantodes pumilum (Primulaceae) has been used in Malaysian folk medicine to help women regain strength after delivery and for "sickness in the bones." It was previously revealed that its extracts inhibited xanthine oxidase (XO) activity in vitro. The leaves and roots of M. pumilum var. alata (MPA), var. pumila (MPP), and var. lanceolata (MPL) were individually extracted in ethanol (80%). The anti-hyperuricemic activity was initially assessed by XO inhibition with a spectrophotometric in vitro assay. The most active extract was further investigated on hyperuricemic rat model induced by potassium oxonate to determine serum uric acid levels and liver XO effect. The in vitro anti-inflammatory activity was carried out on monosodium urate (MSU) crystal-induced pro-inflammatory cytokines (i.e., interleukin (IL)1?, IL-1?, IL-6, IL-8, and tumor necrosis factor (TNF)-?) secretion using human peripheral blood mononuclear cells and ELISA technique, and prostaglandin E2 (PGE2)secretion using radioimmunoassay. The active extract was then investigated on gout-induced inflammation with MSU crystals to determine pro-inflammatory cytokines and PGE2 secretion levels in the synovial fluid of rat knee joint. Quantitative analysis using validated HPLC was performed on the extracts to determine presence of bioactive flavonoids. The findings revealed that extract of MPP leaves gave the highest inhibitory activity on XO (IC50 130.5 ?g/mL) compared to other extracts tested. However, all extracts possessed significantly lower activity compared to allopurinol (IC50 0.13 ?g/mL). Oral administration of MPP leaf extract (200 mg/kg) significantly reduced serum uric acid level in hyperuricemic rats in time-dependent manner to the baseline level and it was as effective as allopurinol (5 mg/kg). The extract also inhibited liver XO activity (25%) compared to allopurinol (45%). In vitro anti-inflammatory assay showed that extract of MPP roots inhibited MSU crystals-induced secretion of IL-1?, IL-1?, IL-8, TNF-?, and PGE2 with IC50 values of 36, 25, 38, 18, and 46 ?g/mL, respectively. Oral administration of the MPP root extract (200 mg/kg) significantly decreased IL-1?, IL-1?, IL-6, TNF-?, and PGE2 levels in rat's synovial fluid as effective as indomethacin. There were no significant body weight changes of all experimental animals. MPP extracts showed presence of myricetin, quercetin and kaempferol. Myricetin was detected with values of 0.2 and 0.6 mg/g for root and leaf extracts, respectively. The anti-hyperuricemic of MPP leaf and anti-inflammatory of MPP root indicated that MPP may be promising for complementary therapy of gout.

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IFN? is a potent anti-influenza therapeutic without the inflammatory side effects of IFN? treatment.

Publications

IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment.

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