1. Approaching Inflammation Paradoxes-Proinflammatory Cytokine Blockages Induce Inflammatory Regulators.
- Author
-
Liu M, Saredy J, Zhang R, Shao Y, Sun Y, Yang WY, Wang J, Liu L, Drummer C 4th, Johnson C, Saaoud F, Lu Y, Xu K, Li L, Wang X, Jiang X, Wang H, and Yang X
- Subjects
- Animals, Data Mining, Databases, Nucleic Acid, Humans, Inflammation immunology, Inflammation pathology, Mice, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Cytokines antagonists & inhibitors, Cytokines immunology, Immunity, Innate drug effects, Signal Transduction drug effects, Signal Transduction immunology, Up-Regulation drug effects, Up-Regulation immunology
- Abstract
The mechanisms that underlie various inflammation paradoxes, metabolically healthy obesity, and increased inflammations after inflammatory cytokine blockades and deficiencies remain poorly determined. We performed an extensive -omics database mining, determined the expressions of 1367 innate immune regulators in 18 microarrays after deficiencies of 15 proinflammatory cytokines/regulators and eight microarray datasets of patients receiving Mab therapies, and made a set of significant findings: 1) proinflammatory cytokines/regulators suppress the expressions of innate immune regulators; 2) upregulations of innate immune regulators in the deficiencies of IFNγ/IFNγR1, IL-17A, STAT3 and miR155 are more than that after deficiencies of TNFα, IL-1β, IL-6, IL-18, STAT1, NF-kB, and miR221; 3) IFNγ, IFNγR and IL-17RA inhibit 10, 59 and 39 proinflammatory cytokine/regulator pathways, respectively; in contrast, TNFα, IL-6 and IL-18 each inhibits only four to five pathways; 4) The IFNγ-promoted and -suppressed innate immune regulators have four shared pathways; the IFNγR1-promoted and -suppressed innate immune regulators have 11 shared pathways; and the miR155-promoted and -suppressed innate immune regulators have 13 shared pathways, suggesting negative-feedback mechanisms in their conserved regulatory pathways for innate immune regulators; 5) Deficiencies of proinflammatory cytokine/regulator-suppressed, promoted programs share signaling pathways and increase the likelihood of developing 11 diseases including cardiovascular disease; 6) There are the shared innate immune regulators and pathways between deficiency of TNFα in mice and anti-TNF therapy in clinical patients; 7) Mechanistically, up-regulated reactive oxygen species regulators such as myeloperoxidase caused by suppression of proinflammatory cytokines/regulators can drive the upregulation of suppressed innate immune regulators. Our findings have provided novel insights on various inflammation paradoxes and proinflammatory cytokines regulation of innate immune regulators; and may re-shape new therapeutic strategies for cardiovascular disease and other inflammatory diseases., (Copyright © 2020 Liu, Saredy, Zhang, Shao, Sun, Yang, Wang, Liu, Drummer, Johnson, Saaoud, Lu, Xu, Li, Wang, Jiang, Wang and Yang.)
- Published
- 2020
- Full Text
- View/download PDF