API

Event: 1571

Key Event Title

?

Decreased IL-1 production

Short name

?

Decreased IL-1 production

Biological Context

?

Level of Biological Organization
Cellular

Cell term

?

Cell term
macrophage


Organ term

?

Organ term
immune system


Key Event Components

?

Process Object Action

Key Event Overview


AOPs Including This Key Event

?


Stressors

?


Taxonomic Applicability

?

Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Life Stages

?

Life stage Evidence
All life stages High

Sex Applicability

?

Term Evidence
Unspecific High

Key Event Description

?


Decreased IL-1 production by macrophages can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β which leads to decreased IL-1b secretion. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan(VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr, 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017). These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β production.


How It Is Measured or Detected

?


Inhibition of IL-1 mRNA expression is measured by quantitative real-time polymerase chain reaction. The production of IL-1β is measured by ELISA (Karpenko et al., 2018).


Domain of Applicability

?


Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known. 

The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.


Evidence for Perturbation by Stressor



References

?


Fenini, G., Contassot, E., French, L.E., 2017. Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front Pharmacol 8, 278.

Finch-Arietta, M.B., Cochran, F.R., 1991. Cytokine production in whole blood ex vivo. Agents Actions 34, 49-52.

Ho, S.C., Chang, Y.H., Chang, K.S., 2018. Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23.

Huang, H., Wang, Y., 2017. The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63, 58-63.

Jeon, Y.J., Han, S.H., Lee, Y.W., Lee, M., Yang, K.H., Kim, H.M., 2000. Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48, 173-183.

Karpenko, M.N., Vasilishina, A.A., Gromova, E.A., Muruzheva, Z.M., Bernadotte, A., 2018. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-alpha levels in CSF and serum in relation to the clinical diversity of Parkinson's disease. Cell Immunol 327, 77-82.

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

Morand, E.F., Rickard, D., Goulding, N.J., 1993. Lack of involvement of lipocortin 1 in dexamethasone suppression of IL-1 release. Mediators Inflamm 2, 49-52.

Qiu, H.B., Pan, J.Q., Zhao, Y.Q., Chen, D.C., 1997. Effects of dexamethasone and ibuprofen on LPS-induced gene expression of TNF alpha, IL-1 beta, and MIP-1 alpha in rat lung. Zhongguo Yao Li Xue Bao 18, 165-168.

Ravizza, T., Lucas, S.M., Balosso, S., Bernardino, L., Ku, G., Noe, F., Malva, J., Randle, J.C., Allan, S., Vezzani, A., 2006. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47, 1160-1168.

Stack, J.H., Beaumont, K., Larsen, P.D., Straley, K.S., Henkel, G.W., Randle, J.C., Hoffman, H.M., 2005. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175, 2630-2634.

van Furth, A.M., Seijmonsbergen, E.M., Langermans, J.A., van der Meide, P.H., van Furth, R., 1995. Effect of xanthine derivates and dexamethasone on Streptococcus pneumoniae-stimulated production of tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-10 by human leukocytes. Clin Diagn Lab Immunol 2, 689-692.

Vincent, J.A., Mohr, S., 2007. Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56, 224-230.

Wang, A.L., Yu, A.C., Lau, L.T., Lee, C., Wu le, M., Zhu, X., Tso, M.O., 2005. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47, 152-158.

Weinberg, J.B., Mason, S.N., Wortham, T.S., 1992. Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79, 3337-3343.

Xu, F., Wang, F., Wen, T., Sang, W., Wang, D., Zeng, N., 2017. Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39, 296-304.