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    • Previous studies have shown that HER

    2022-04-11

    Previous studies have shown that HER2 is also involved in IL-6 expression and signaling. IL-6, HER2, and GP130, the beta-subunit of the IL-6 receptor (IL-6R), are physically associated and co-immunoprecipitate in response to IL-6 stimulation [1]. IL-6 induced HER2 clustering to the GP130 complex, led to HER2 transphosphorylation, and HER2 activation of Shc/MAP kinase pathway [29]. In addition, overexpression of HER2 in breast cancer cell lines led to increased IL-6 secretion which was decreased with HER2 inhibitors [30]. These findings point to a critical interaction between HER2 and IL-6.
    Materials and methods
    Results
    Discussion Lung inflammation leading to ALI and acute respiratory distress syndrome (ARDS) are major problems that carry a high morbidity and mortality. Estimates based on the National Heart Lung and Blood Institute's ARDS Network studies found an incidence of ∼150,000 cases/year of ALI and ARDS in the U.S. [33]. In mechanically ventilated patients, 10–20% develop ALI or ARDS [34]. Associated with these diagnoses are mortality rates reported between 35% and 60%. Understanding how the inflammatory process is regulated in the lung could be a key to designing new therapeutic strategies to prevent or minimize these processes. In large clinical trials biomarkers to predict the outcome of lung injury have found IL-6 plasma levels to be predictive of higher morbidity [15] and mortality [28]. In addition, circulating levels of IL-6 are predictors of ARDS severity in sepsis and acute pancreatitis [35,36]. NRG-1 in BAL has also been shown to be a predictor of morbidity in ARDS, and the NRG-1/HER2 axis has a role in regulating the alveolar capillary barrier [2,3,15,37]. Importantly, the NRG-1/HER2 and the IL-6/IL-6R signaling axes have been shown to be interconnected in skeletal muscle [38], endothelial Bryostatin 1 [39], prostate and breast carcinoma [1,32], and we provide new data in these studies to include pulmonary epithelial cells showing that IL-6 leads to HER2 transphosphorylation and HER2 activation. Importantly, we have found that in pulmonary epithelial cells the HER2 and IL-6 receptor complexes are physically associated with IL-6R, GP130 and HER2 co-immunoprecipitating and localized together on the cell surface and intracellularly. In addition, the presence of IL-6 and GP130 are required for NRG-1 signaling through HER2. Thus, the coordination of IL-6 and NRG-1 is essential for activation of the HER2 signaling pathway. Further, NRG-1 and HER2 significantly increased the amount of IL-6 released by pulmonary epithelial cells. The increase in IL-6 seems to be due to both an increase in gene expression as evidenced by the effect of shRNA mediated transcript knockdown, and potentially by increased membrane shedding. MMP1, MMP3, and MMP10 are induced by IL-6, and MMP7 is induced by HER2. Our prior studies have shown that metalloproteinases are required for membrane bound NRG-1 shedding [3,40] and are also required for IL-6 membrane shedding. This sets up an autocrine/paracrine feedback loop consisting of an IL-6 requirement for NRG-1 induced HER2 signaling, leading to increased IL-6 secretion/shedding that may further allow NRG-1 as well as IL-6 induced signaling. Our prior studies showing that the NRG-1/HER2 signaling axis is injurious in the lung [3,5,37] and correlates with injury in patients [15], in conjunction with the current data showing an IL-6 requirement for NRG-1 induced HER2 activation, clearly shows an active NRG-1/HER2/IL-6 signaling loop in ALI/ARDS. Similar feedback loops and enhanced effects have been identified between IL-6/IL-6R and HER2 signaling in cancer. HER2 overexpression in breast cancer resulted in elevation of IL-6 gene expression, HER2 induced secretion of IL-6, autocrine STAT3 signaling, and enhanced HER2 mediated transformation [30]. This autocrine feedback loop is similar to what we report here and the mechanisms build on our previous work showing NRG-1 signals through STAT 3 [29]. Thus, a constitutive requirement for IL-6 in NRG-1 induced HER2 signaling, and the resultant HER2 induced IL-6 secretion and STAT3 signaling provide a possible molecular basis for the pathologic inflammatory markers seen in lung injury and the association with disease severity. This suggests that IL-6 targeted therapies could have significant impact on lung disease marked by HER2 activation as we have shown in ARDS [15].