Streptococcus pneumoniae autolysin LytA inhibits ISG15 and ISGylation through decreasing bacterial DNA abnormally accumulated in the cytoplasm of macrophages.

Interferon stimulated gene 15 (ISG15) is one of the most robustly upregulated interferon stimulated genes (ISGs) and also a ubiquitin-like modifier which has been reported to play an important role in host defense against pathogens. Cytosolic nucleic acids detected by DNA sensors induce type Ⅰ interferons (IFN-Ⅰs) and ISGs in host cells. Streptococcus pneumoniae (S. pn) autolysin LytA triggers bacterial lysis and then S. pn-derived genomic DNA (hereafter referred to as S. pn-DNA) can be released and accumulates in the cytoplasm of host cells. However, it remains elusive whether LytA-mediated S. pn-DNA release is involved in ISG15 induction. Here we verified that ISG15 conjugation system can be widely activated by S. pn and cytosolic S. pn-DNA in host cells. Moreover, the phagocytosis of macrophages to the mutant strain S. pn D39 ΔlytA was enhanced when compared to S. pn D39, which in turn increased S. pn-DNA uptake into macrophages and augmented ISG15 expression. ISG15 might upregulate proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) in macrophages and further promoted the clearance of S. pn in the absence of LytA. These results indicate that S. pn autolysis blunts ISG15 induction through preventing bacteria internalization and reducing cytosolic S. pn-DNA accumulation in macrophages, revealing a new strategy of S. pn for avoiding elimination. This study will help us to further understand the role of ISG15 during S. pn infection as well as the regulatory mechanisms of immune responses mediated by bacterial autolysis and bacterial DNA.

IL-33 synergistically promotes the proliferation of lung cancer cells in vitro by inducing antibacterial peptide LL-37 and proinflammatory cytokines in macrophages.

Lung cancer is the primary cause of cancer-related deaths, and the persistent inflammation is inextricably linked with the lung cancer tumorigenesis. Pro-inflammatory cytokine interleukin-33 (IL-33) is able to serve as a potent modulator of cancer. Mounting evidence indicates IL-33 has significant effect on lung cancer progression by regulating host immune response, but the current opinions about the function and mechanism of IL-33 in lung cancer are still controversial. Meanwhile, antibacterial peptide LL-37 also exerts a momentous effect on immune responses to lung cancer. LL-37 is regarded as versatile, including antimicrobial activities, chemotaxis and immunoregulation. However, the immunomodulatory mechanism of IL-33 and LL-37 in lung cancer remains thoroughly not defined. Here, we determined the secretion of LL-37 was up-regulated in lung cancer serum samples. Similarly, the expression of CRAMP was enhancive in macrophages after co-cultured with lung cancer cells. Moreover, we expounded that IL-33 could up-regulate LL-37 secretion in macrophages, resulting in the massive releases of IL-6 and IL-1ß. Additionally, LL-37 cooperated with IL-33 to increase the phosphorylation of p38 MAPK and NF-κB p65 pathways, and augmented IL-6 and IL-1ß secretion, which resulting in the proliferation of lung cancer cells in vitro. In conclusion, our study identified that IL-33 aggravated the inflammation of lung cancer by increasing LL-37 expression in macrophages, thereby promoting lung cancer cell proliferation in vitro. It is contributed to our present understanding of the immunomodulatory relationship between pro-inflammatory cytokines and antibacterial peptides in the tumor immune response, and offer a novel perspective for controlling the progress of lung cancer.