Alveolar Epithelial STAT3, IL-6 Family Cytokines, and Host Defense during Escherichia coli Pneumonia

Abstract

While signal transducer and activator of transcription (STAT) 3 signaling has been linked to multiple pathways influencing immune function and cell survival, the direct influence of this transcription factor on innate immunity and tissue homeostasis during pneumonia is unknown. Human patients with dominant-negative mutations in the Stat3 gene develop recurrent pneumonias, suggesting a role for STAT3 in pulmonary host defense. We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram-negative bacterial pneumonia. STAT3 phosphorylation was increased in pneumonic mouse lungs and in murine lung epithelial (MLE)-15 cells stimulated with pneumonic bronchoalveolar lavage fluid (BALF) through 48 hours of Escherichia coli pneumonia. Mice lacking active STAT3 in alveolar epithelial cells (Stat3 D/D ) had fewer alveolar neutrophils and more viable bacteria than control mice early after intratracheal E. coli. By 48 hours after E. coli infection, however, lung injury was increased in Stat3 D/D mice. Bacteria were cleared from lungs of both genotypes, albeit more slowly in Stat3 D/D mice. Of the IL-6 family cytokines measured in lungs from infected C57BL/6 mice, IL-6, oncostatin M, leukemia inhibitory factor (LIF), and IL-11 were significantly elevated. Neutralization studies demonstrated that LIF and IL-6 mediated BALF-induced STAT3 activation in MLE-15 cells. Together, these results indicate that during E. coli pneumonia, select IL-6 family members activate alveolar epithelial STAT3, which functions to promote neutrophil recruitment and to limit both infection and lung injury.Keywords: lung; neutrophils; STAT3; pneumonia; cytokines Lung infections account for a tremendous burden of disease worldwide and are a leading cause of acute lung injury (1, 2). While Streptococcus pneumoniae is the most common agent in patients with community-acquired pneumonia (3), gram-negative rods such as Escherichia coli are a frequent cause of nosocomial pneumonia (4). Elimination of these and other pathogens from the lower respiratory tract is made possible by an effective innate immune response (5), which is necessary yet potentially dangerous to the infected host. For this reason, cytokine networks, neutrophil emigration, plasma extravasation, and other characteristics of acute inflammation must be precisely regulated to maintain tissue homeostasis.The STAT3 transcription factor influences both immunity and inflammatory injury, but the importance of STAT3 signaling during pneumonia is unknown. STAT3 activity has been attributed both inflammatory (6-9) and anti-inflammatory (10-12) roles. Likewise, the cytokine interleukin (IL)-6, which largely signals through STAT3 (13, 14), has also been described as both pro-(15-19) and anti-inflammatory (16, 20-22), depending on the biological context. During E. coli pneumonia, neutrophil recruitment and bacterial clearance are impaired in IL-6-deficient mice (15). While the mechanisms through which IL-6 functions during this i...

Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity

“…Consistent with the functional plasticity of NK-22 cells, a recent study showed that LTilike cells isolated from human tonsils and cultured in IL-2 secrete IFN-γ (9). Interestingly, our results show that IL-2 also may be an important factor in promoting the secretion of LIF, a cytokine that has been shown to protect epithelial cells against bacterial infections (20). The functional deviation of NK-22 cells toward IFN-γ production is reminiscent of that of T H 17 T cells, which also can convert into IFN-γ-producing T H 1 T cells (23)(24)(25)(26).…”

“…We previously reported that NK-22 cells produce LIF (1), a cytokine that has been reported to protect the mucosal barriers (20). To determine whether cultured NK-22 cells produce LIF, we measured LIF released in supernatants by ELISA.…”

Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A

“…The central role of the type I IFN in the host defense against viral infection has been well documented and is implicated in the pathogenesis of several bacterial infections (16,23,36). The many consequences of this cascade and its importance in linking the innate and adaptive immune response are the subject of numerous reviews (12,22).…”

“…Induction of IFN-α family members was not detected. Production of IFN-β-dependent gene products was also observed: USA300 induced a 7-fold increase in Mx-1, a prototypical type I IFN antiviral effector, a 130-fold increase in IL-6, and a 4-fold increase in Lif, a gene product that is important in host defense in the lung specifically (23). Induction of these IFN-dependent gene products was significantly attenuated in the absence of SpA (Figure 1A).…”

Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

“…Virtually all cells bear the IL-17 receptor, which has been shown to recruit neutrophils to the lung by stimulating the production of the ELR1CXC chemokines, IL-8 or KC (a mouse homolog of IL-8) (57), and G-CSF. In addition, IL-17A seems to be important for the early and the late phase of neutrophil accumulation in the lungs (52). Furthermore, IL-17 can induce the up-regulation of other cytokines, including IL-1b and IL-6, and ICAM-1 by several types of cells (e.g., endothelial cells, epithelial cells) (57).…”