Interleukin-1β is the primary initiator of pulmonary inflammation following liver injury in mice

Abstract

Hepatic injury can lead to systemic and pulmonary inflammation through activation of NF-κB-dependent pathways and production of various proinflammatory cytokines. The exact mechanism remains unknown, although prior research suggests interleukin-1β (IL-1β) plays an integral role. Cultured murine alveolar macrophages were used to identify an optimized IL-1β-specific short interfering RNA (siRNA) sequence, which then was encapsulated in liposomes and administered intraperitoneally to transgenic HLL mice (5′-HIV-LTR-Luciferase). A 35% hepatic mass cryoablation in HLL and IL-1 receptor 1 knockout mice (IL1R1KO) was performed as a model for liver-induced pulmonary inflammation. IL-1β siRNA pretreatment effectively and significantly reduced circulating IL-1β levels at 4 h post-hepatic injury. IL-6 also was suppressed in mice with impaired IL-1 signaling pathways. NF-κB activation in the noninjured liver of HLL reporter mice pretreated with IL-1β siRNA was found to be reduced compared with controls. Pulmonary NF-κB activity in this group also was diminished relative to controls. C-X-C chemokine levels in the lung remained significantly lower in IL-1 pathway-deficient mice. Similarly, lung myeloperoxidase content was unchanged from baseline at 24 h post-liver injury in IL-1β siRNA-treated animals, whereas all other control groups demonstrated marked pulmonary neutrophilic infiltration. In conclusion, liver injury-induced lung inflammation in this model is mediated predominantly by IL-1β. Knockdown of IL-1β expression before hepatic injury led to significant reductions in both cytokine production and NF-κB activation. This translated to reduced pulmonary neutrophil accumulation. Pretreatment with IL-1β siRNA may represent a novel intervention for preventing liver-mediated pulmonary inflammation.

Lung Natural Killer Cells Play a Major Counter-Regulatory Role in Pulmonary Vascular Hyperpermeability After Myocardial Infarction

“…IL-1β is not a direct chemoattractant for neutrophils, but it mediates neutrophil recruitment through the synthesis of IL-6, ICAM-1, and CXCL-1. 14 We confirmed that IL-1β stimulated the expression of IL-6, ICAM-1, and CXCL-1 in lung-ECs ( Figure 3F-H) and neutrophil adhesion to lung-ECs ( Figure 3I and 3J), both of which were blocked by IL-1R1 antibody-mediated neutralization. The increase in lung IL-6, ICAM-1, CXCL-1 expression after MI was also blocked by IL-1R1 antibody, and IL-1β stimulated lung IL-6, ICAM-1, and CXCL-1 expression in the absence of MI ( Figure 3K-M).…”

Role of Aspergillus fumigatus DvrA in Host Cell Interactions and Virulence

“…These results suggested that the increased mortality of nonneutropenic mice infected with this mutant is due in part to an overexuberant inflammatory response. To investigate this possibility, we determined the pulmonary fungal burden, as well as pulmonary levels of MPO (a marker of phagocyte accumulation [12,40]) and proinflammatory cytokines, in these mice. After 4 days of infection, the pulmonary galactomannan content of mice infected with the ⌬dvrA mutant was significantly higher than that of mice infected with the wild-type strain (P ϭ 0.018), but not that of mice infected with the ⌬dvrA::dvrA-complemented strain (P ϭ 0.21) (Fig.…”

“…The MPO content was used to assess the accumulation of phagocytes during infection (12,40). The MPO levels in the lung homogenates were measured by enzyme immunoassay (Cell Sciences).…”

Anti-inflammatory effect of resveratrol in old mice liver

“…This organ is considered one of the main sources of proinflammatory cytokines in chronic systemic inflammation associated with aging and related to chronic age-related diseases (Aravinthan et al, 2014;Glasgow et al, 2007). In the present work, we study the effect of RSV in systemic inflammation as a function of age in mouse liver and assess whether RSV modulates these effects.…”

“…In this systemic inflammatory status, the liver has being indicated as playing a central role. This is because, the liver not only contains the greatest concentration of the body's resident tissue macrophages, the Kupffer cells, but hepatocytes can also be a main source of a variety of proinflammatory cytokines (Glasgow et al, 2007).…”