Lost in Trans-IL-6 Signaling: Alveolar Type II Cell Death in Emphysema

In this issue of the Journal, Ruwanpura and colleagues (pp. 1494–1505) identify IL-6 trans-signaling (IL-6 TS; Figure 1) as a potential therapeutic target to inhibit alveolar epithelial cell death and preserve lung parenchymal structure and function (1). The substantial impact of these findings relies on the use of complementary transgenic and pharmacological approaches to inhibit IL-6 TS in animal models, combined with fingerprinting similar patterns of signaling molecules in human lungs with emphysema. The study does not exclude a contribution of classical IL-6 signaling to emphysema development; rather, it focuses on the proapoptotic effects of gp130 gain of function either by transgenic overexpression or in the context of acute and subchronic (3 mo) cigarette smoke exposure. Either soluble gp130 (sgp130) overexpression or administration of sgp130-Fc protein prevented airspace enlargement and improved static lung compliance in the two murine models studied. The interest in targeting IL-6 TS in emphysema is not surprising, given that this approach has been quite successful in reducing chronic inflammation in murine models of rheumatologic, central nervous system, allergic, and gastrointestinal disease (2).

Figure 1.

Schematic of IL-6 trans-signaling pathway involvement in lung cell apoptosis and emphysema-like disease. Ruwanpura and colleagues (1) have demonstrated that inhibitors of IL-6 trans-signaling ameliorate apoptosis and emphysema-like phenotype induced by either cigarette smoke or by transgenic overexpression of gp130. These effects were associated with increased mechanistic target of rapamycin complex 1 (MTORC1) signaling and were inhibited by rapamycin. ATII = alveolar type II cells; MGK = megakaryocytes; sIL-6R = soluble IL-6 receptor; sgp130 = soluble gp130; TACE = ADAM 17.

The sgp130 augmentation approaches employed by Ruwanpura and colleagues to attenuate IL-6 TS activation in the lung had an impressive inhibitory effect on apoptosis; in particular, preventing alveolar type II (ATII) cell loss. This finding, from the group that first identified an association of IL-6 TS with airspace remodeling (3), supports the now well-accepted notion that alveolar cell fitness and survival are critically important to the maintenance of the integrity of alveolar structures (4). The demonstration that IL-6 TS was necessary and sufficient for inducing ATII cell apoptosis and an emphysema-like phenotype solidifies the notion that unrepaired loss of lung epithelial cells is associated with airspace destruction and increased lung compliance. These results add IL-6 TS to the list of several mechanisms, such as those mediated by innate antiviral immune responses (5) or by augmentation of Fas–Fas ligand interaction (6), that trigger lung epithelial cell death associated with airspace enlargement. The role of IL-6 TS in initiating cell death of other structural lung parenchymal cells essential to alveolar maintenance, such as microvascular endothelial cells, remains to be explored. Although it would be alluring to infer that lung endothelial cells, which also express gp130, respond to IL-6 TS similar to ATII, reports point to potential cell-type specific responses. As an example, sgp130-Fc, rather than protecting from apoptosis, actually sensitized T cells to undergo cell death and improved outcomes in a murine model of experimental colitis (7). Although inhibition of inflammation was not noted as a main effect of IL-6 TS in the lung parenchyma in Ruwanpura and colleagues’ work, the effect of IL-6 TS on inflammatory cell function in emphysema warrants further investigation. Furthermore, given the pleiotropic signaling induced by IL-6 TS (8–10), the activation of this pathway may extend beyond apoptosis and inflammatory cell modulation to other pathobiological mechanisms of importance to emphysema development such as senescence, mucus hypersecretion, and autoimmunity. Evidence of involvement of IL-6 TS in these processes in the lung will only magnify the interest to targeting this pathway to improve chronic obstructive pulmonary disease and emphysema outcomes.

In addition to the high potential for translation to bedside, the work by Ruwanpura and colleagues pointed to several interesting signaling responses to IL-6 TS activation. The finding that IL-6 TS activated ADAM-17 (TACE), a protease that cleaves gp130 to generate the ectodomain inhibitory molecule sgp130, indicated a potential autocrine negative feedback loop triggered by IL-6 TS. However, TACE, by cleaving IL-6 receptor (11), whose expression is restricted to only several cell types, including leukocytes, can also shed soluble IL-6 receptor, which serves to activate IL-6 TS, thus engaging a paracrine/endocrine positive feedback loop. Further, TACE has multiple other membrane receptor targets (12) (tumor necrosis factor α, epidermal growth factor receptor, selectins, or Fas ligand, among others) that may contribute to the effects reported here. The relative contribution, magnitude, and kinetics of these responses should be considered to better distinguish pathogenic from compensatory responses of lung cells facing chronic exposure to cigarette smoking.

Also intriguing was the fact that IL-6 TS activation triggered mechanistic target of rapamycin and its downstream ribosomal protein S6 kinase (S6) signaling, which was linked to apoptosis of ATII cells. The effect of this typically prosurvival signaling pathway on lung apoptosis and remodeling was mechanistically interrogated using rapamycin, a classical inhibitor of mechanistic target of rapamycin complex 1 (MTORC1). In mice exposed to cigarette smoking or to IL-6 TS hyperactivation, Rapamycin was protective, inhibiting apoptosis and airspace enlargement, simultaneously with the predictable inhibition on S6 phosphorylation. Although at first glance straightforward, the interpretation of these results in the context of other published reports reflects the intricate nature of the effects of rapamycin on normal and diseased lungs. Apart from indirect effects on MTORC2, the effects of rapamycin are highly dependent on the biological context of MTORC1 activation, the magnitude and duration of activation, and the downstream effectors engaged. In addition to protein synthesis and proliferation typically associated with survival, this pathway inhibits autophagy and regulates metabolic and mitochondrial functions, as well as aging (13). This complex involvement reconciles the findings that at certain doses, rapamycin had beneficial antiapoptotic effects during IL-6 TS hyperactivation in relatively older (6 mo of age) mice reported here, while being previously reported proapoptotic in otherwise healthy mice or antiinflammatory during acute cigarette smoke exposure of younger (3 mo of age) mice (14). In addition, in the absence of direct interrogation, the involvement of S6 activation in lung cell apoptosis remains speculative. Typically engaged by MTORC, along with 4E-binding protein 1, to stimulate protein synthesis, the activity of S6 in the lung may be contributed by surviving cells that withstand apoptotic stress or by those involved in repair. For example, compared with cells from nonsmokers, cultured primary microvascular endothelial cells from smokers exhibited significant up-regulation of signaling molecules associated with survival and had adapted to better withstand apoptotic stimuli (15). Further, given a recent report of involvement in lung carcinogenesis (16), it is conceivable that prolonged IL-6 TS-induced signaling may lead to both apoptosis and inappropriate cell proliferation, with potential relevance to the increased lung cancer risk in those suffering from emphysema.

Notwithstanding validation in other preclinical models, this is the first report to mechanistically link emphysema to IL-6 TS and offer a promising strategy to ameliorate apoptosis in emphysematous lungs by using IL-6 TS inhibitors.