Effect of tumor necrosis factor-α-induced proteinï¿½8 on the immune response of CD4+ Tï¿½lymphocytes in mice following acute insult

Cationic lipid-mediated intravenous gene delivery shows promise in treating pulmonary diseases including lung tumor metastases, pulmonary hypertension, and acute respiratory distress syndrome. Nevertheless, clinical applications of cationic lipidic vectors via intravenous administration are limited by their transient gene expression. In addition, repeated dosing is not effective at frequent intervals. In an effort to elucidate the mechanism of gene inactivation, we report in this study that cationic lipid-protamine-DNA (LPD) complexes, but not each component alone, can induce a high level of cytokine production, including interferon-γ and tumor necrosis factor-α. Furthermore, we demonstrate that LPD administration triggers apoptosis in the lung, a phenomenon that may be mediated in part by the two cytokines. Treatment of mice with antibodies against the two cytokines prolongs the duration of gene expression and also improves lung transfection on a second administration of LPD. Although the mechanism underlying LPD-induced cytokine production is unclear, methylation of the DNA significantly decreased the level of both interferon-γ and tumor necrosis factor-α, suggesting that unmethylated CpG sequences in plasmid DNA play an important role. These data suggest that decreasing the CpG-mediated immune response while not affecting gene expression may be a useful therapeutic strategy to improve cationic lipid-mediated intravenous gene delivery to the lung.

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FEATURES OF THE IMMUNE RESPONSE FORMATION TO THERMAL TRAUMA

Fiziolohichnyĭ zhurnal ◽

10.15407/fz67.06.032 ◽

2021 ◽

Vol 67 (6) ◽

pp. 32-39

Author(s):

O.M. Lynnyk ◽

◽

O.I. Osadcha ◽

H.P. Kozynets ◽

I.R. Yanchiy ◽

...

Keyword(s):

Immune Response ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Burn Injury ◽

Neutrophilic Granulocytes ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Necrosis Factor

To study the effect of thermal trauma on the immune response formation, 43 patients aged 16 to 58 with body surface area of burns 20-60% were examined. The neutrophilic granulocytes (NG) and monocytes functional activity, the content of myeloperoxidase and substances with a positive reaction to Schiff’s periodic acid (PAS- stained substances), the cytokines content were determined: interleukin-1β (IL-1β), IL-2, IL-4, IL- 6, tumor necrosis factor-α (TNF-α). Thermal damage caused changes in the immune response, which were characterized by a pro-inflammatory phase in which innate immunity cells (neutrophilic granulocytes, monocytes) acquired high functional activity, producing a higher content of proinflammatory cytokines. On the 2-3rd day after the burn injury in the peripheral blood, the interleukin-1β (IL-1β) content was 133.5 ± 21.1 pg/ml, the tumor necrosis factor α (TNF-α) content was 265 ± 115.5 pg/ml, which exceeded the reference values by 5.1 and 10.9 times, respectively. The content of IL-6 on the 2-3rd day was 85.30 ± 13.10 pg/ml. Also a concomitant syndrome of compensatory anti-inflammatory response developed with increasing production of anti-inflammatory IL-4: on the 2-3rd day after burn injury, its content was 268.5 pg/ml, exceeding the reference values by 8.2 times. The content of anti-inflammatory IL-10 was decreased. This suggests that anti-inflammatory cytokines do not compensate for the high content of pro-inflammatory factors. On the 7th-8th day after the burn injury, there was a tendency to further increase the content of pro-inflammatory cytokines IL- 1β and TNF-α to 148.0 ± 27.0, and 281.2 ± 146.7 pg/ml, respectively, while the content of IL-6 on the 7-8th day was 131.0 ± 11.1 pg/ml, the anti-inflammatory cytokine IL-10 increased slightly, and the content of IL-4 decreased. These changes in the early period of burn disease dynamics, as well as reduced activity of myeloperoxidase and PAS- stained substances NG, point for a functional deficiency of NG, reduced enzymatic activity and cells energy resources decompensation. These changes could clinically lead to SIRS progression and multiorgan dysfunction.

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