Home
|
Inbox
|
Search
|
View Abstract
The Histone Deacetylase Inhibitor Trichostatin a Modulates Rhinovirus-Induced Airway Responses in Immature Mice Through IL-1 Receptor Antagonist
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A6226 - The Histone Deacetylase Inhibitor Trichostatin a Modulates Rhinovirus-Induced Airway Responses in Immature Mice Through IL-1 Receptor Antagonist
Author Block: J. K. Bentley, J. L. Hinde, J. Lei, T. Ishikawa, C. Rajput, M. Han, M. B. Hershenson; Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.
Rationale: Rhinovirus (RV) treatment of immature, 6 day-old mice induces an asthma-like mucous metaplasia phenotype. Development of the mucous phenotype is dependent on the innate cytokines IL-25 and IL-33 as well as IL-13 production from type 2 innate lymphoid cells. In contrast to immature mice, mature mice infected with RV fail to show IL-25 expression, ILC2 expansion or mucous metaplasia (Hong et al. J Allergy Clin Immunol 2015). We hypothesized that the differential response of immature mice to RV infection is regulated by histone acetylation. To test this, we investigated the effects of a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) on RV-induced airway responses. HDACs remove acetyl groups from lysine residues, allowing the histones to wrap DNA more tightly, thereby decreasing gene expression.
Methods: Six day-old and 6-8 week-old mature BALB/c mice were inoculated intransally with sham-infected HeLa cell lysate or RV1B. Selected mice were injected with PBS or TSA (2 μg/g IP, 1 hour prior and once/day for 5 days after infection). Other mice were treated with Anakinra, an interleukin-1 receptor antagonist (1 μg/g IP, 1 hour prior and 24 hours after infection). Cytokine expression and mucous production were assessed by qPCR, histology and immunofluorescence.
Results: Two days after RV infection, mice treated with TSA showed reduced IL-25 and IL-33 immunostaining and lung mRNA expression. The mucous phenotype was also attenuated. Reasoning that TSA increases the expression of an anti-inflammatory cytokine, we probed samples for expression of IL-1 receptor antagonist (IL1RN). RV infection induced significantly higher IL1RN mRNA and protein expression in mature compared to 6 day-old mice, and TSA treatment of immature mice increased IL1RN expression. Finally, to test whether IL1RN regulates innate cytokine expression, we administered Anakinra prior to and after RV infection. As predicted, Anakinra lowered RV-stimulated transcription of IL-25 and IL-13 while blocking the mucous phenotype.
Conclusion: Compared to mature mice, RV-induced IL1RN expression is repressed in immature mice and increased with TSA treatment. Both TSA and Anakinra inhibit expression of cytokines promoting RV-induced mucous metaplasia. These data suggest that epigenetic regulation of IL1RN plays a role in the age-dependent response to RV infection. Supported by NIH AI120526.
Author Block: J. K. Bentley, J. L. Hinde, J. Lei, T. Ishikawa, C. Rajput, M. Han, M. B. Hershenson; Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.
Rationale: Rhinovirus (RV) treatment of immature, 6 day-old mice induces an asthma-like mucous metaplasia phenotype. Development of the mucous phenotype is dependent on the innate cytokines IL-25 and IL-33 as well as IL-13 production from type 2 innate lymphoid cells. In contrast to immature mice, mature mice infected with RV fail to show IL-25 expression, ILC2 expansion or mucous metaplasia (Hong et al. J Allergy Clin Immunol 2015). We hypothesized that the differential response of immature mice to RV infection is regulated by histone acetylation. To test this, we investigated the effects of a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) on RV-induced airway responses. HDACs remove acetyl groups from lysine residues, allowing the histones to wrap DNA more tightly, thereby decreasing gene expression.
Methods: Six day-old and 6-8 week-old mature BALB/c mice were inoculated intransally with sham-infected HeLa cell lysate or RV1B. Selected mice were injected with PBS or TSA (2 μg/g IP, 1 hour prior and once/day for 5 days after infection). Other mice were treated with Anakinra, an interleukin-1 receptor antagonist (1 μg/g IP, 1 hour prior and 24 hours after infection). Cytokine expression and mucous production were assessed by qPCR, histology and immunofluorescence.
Results: Two days after RV infection, mice treated with TSA showed reduced IL-25 and IL-33 immunostaining and lung mRNA expression. The mucous phenotype was also attenuated. Reasoning that TSA increases the expression of an anti-inflammatory cytokine, we probed samples for expression of IL-1 receptor antagonist (IL1RN). RV infection induced significantly higher IL1RN mRNA and protein expression in mature compared to 6 day-old mice, and TSA treatment of immature mice increased IL1RN expression. Finally, to test whether IL1RN regulates innate cytokine expression, we administered Anakinra prior to and after RV infection. As predicted, Anakinra lowered RV-stimulated transcription of IL-25 and IL-13 while blocking the mucous phenotype.
Conclusion: Compared to mature mice, RV-induced IL1RN expression is repressed in immature mice and increased with TSA treatment. Both TSA and Anakinra inhibit expression of cytokines promoting RV-induced mucous metaplasia. These data suggest that epigenetic regulation of IL1RN plays a role in the age-dependent response to RV infection. Supported by NIH AI120526.
|
Home
|
Inbox
|
Search
|