Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C)

Abstract

Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6-deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD.

Tobacco and e-cigarette products initiate Kupffer cell inflammatory responses

“…Combining all of these findings, it suggests that Kupffer cells may play a significant role in initiating inflammatory responses in the liver and possibly outside of the liver. Again, there is little previous work on the role of tobacco products and ecigarette products on Kupffer cell health, however, similar cytokine release profiles have been observed after macrophage exposure to cigarette products (Hubeau et al, 2013;John-Schuster et al, 2014;Kubo et al, 2005;Pauwels et al, 2011;Shen et al, 2014).…”

Antibody treatment against pulmonary exposure to abrin confers significantly higher levels of protection than treatment against ricin intoxication

“…While anti-abrin antibody treatment at 24 h PE brought about a 90% reduction in IL-6 levels by 72 h PE, application of anti-ricin antibodies to ricin-intoxicated mice did not affect IL-6 levels whatsoever and these remained at least as high as in intoxicated mice that were not subjected to antibody treatment. We note in this context, that various studies have documented a positive correlation between IL-6 levels and excessive pulmonary inflammation in pre-clinical models of lung injuries (Hubeau et al, 2013;Yu et al, 2002;Zhang et al, 2013). Thus, one may be tempted to draw a line between the superior ability to protect against abrin intoxication and the fact that antibody treatment uniquely reduces IL-6 levels in mice exposed to this toxin, yet this apparent correlation remains at present circumstantial and should be further probed.…”

IL-6 ameliorates acute lung injury in influenza virus infection

“…Moreover, TGF-β promotes epithelial cells undergoing EMT to become myofibroblasts27.Targeting TGF-β activity and its downstream signaling pathways effectively attenuates fibrosis formation2829. Previous studies have indicated that IL-6 and TGF-β participate in the pathogenesis of lung diseases, such as ARDS30, lung fibrosis, asthma31 and chronic obstructive pulmonary disease32. Influenza virus induces activation of latent TGF-β, which can determine viral pathogenesis and is associated with virus-induced cell apoptosis412.…”