Higher susceptibility of males to bleomycin-induced pulmonary inflammation is associated with sex-specific transcriptomic differences in myeloid cells.

Idiopathic pulmonary fibrosis, a condition with likely genetic and environmental etiology, is relatively more prevalent with poor prognosis in human males. However, the underlying mechanisms for these gender-associated differences in the severity of fibrosis remain unknown. Here, we tested the hypothesis that the transcriptomic repertoire of myeloid cells determines the higher susceptibility of male mice to bleomycin (BLM)-induced lung fibrosis. Adult mice were oropharyngeally challenged with saline or BLM. Lung injury, inflammation, and fibrosis outcomes were assessed, and airspace myeloid-cells were subjected to RNA-sequencing. As compared with the female mice, the male mice manifested significantly increased lung injury, inflammation, proinflammatory cytokines (IL-6, IL-1ß, IL-7, and IP-10), and fibrosis in response to BLM challenge. Interestingly, several pro-inflammatory and extracellular matrix-associated genes were significantly up-regulated in male myeloid-cells compared to female myeloid-cells in the saline-control group. Similarly, BLM challenge resulted in greater pro-inflammatory and pro-fibrotic transcriptomic changes in male compared to female myeloid cells. On the other hand, anti-inflammatory and regulatory cytokine, Il10 and Ifng respectively, were uniquely upregulated in BLM-challenged female but not in male myeloid cells when compared to their respective saline-control groups. Further, cross-sex bone marrow transplantation experiments revealed that male hematopoietic progenitor cells (HPCs) increased the granulocytic infiltration in female mice while female HPCs decreased the granulocytic infiltration in male mice post-BLM challenge. These findings suggest that there are inherent transcriptomic differences between the male and female lung myeloid cells and that the pro-inflammatory nature of male myeloid cells is sufficient to increase the susceptibility of female mice to BLM-induced inflammation.

Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma.

Inflammatory biomarkers, such as the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and Glasgow Prognostic Score (GPS) have been proposed to predict prognosis in diffuse large B-cell lymphoma (DLBCL). C-X-C motif ligand 10 (CXCL10) is a chemokine released from inflammatory cells in the tumor microenvironment and is known to promote tumor cell migration and invasion. In this study, we investigated the clinical impact of pretreatment serum level of CXCL10 on the prognostic value of inflammatory biomarkers in 313 patients with DLBCL who were enrolled into a prospective cohort study. Serum level of CXCL10 was measured in archived pretreatment frozen samples. The high CXCL10 (>median value) group was significantly associated with high tumor burden status, including advanced stage (III-IV), elevated serum lactic dehydrogenase, and a higher risk International Prognostic Index. Progression-free survival of the high CXCL10 group was significantly worse than that of the low CXCL10 group, and secondary central nervous system involvement was more frequent in the high CXCL10 group. High CXCL10 was associated with high C-reactive protein level (r = 0.246), low albumin level (r = -0.289), low absolute lymphocyte count (r = -0.185), and risk stratification according to NLR, LMR, and GPS. C-X-C motif ligand 10 promoted cell migration of patient-derived cells and several DLBCL cell lines. However, the prognostic value of high CXCL10 was lost in the multivariate analyses. Nevertheless, we suggest serum CXCL10 may have clinical value if it can be more easily assessed because of its contribution to the prognostic value of NLR, LMR, and GPS in DLBCL.

Synergistic antitumor effect of CXCL10 with hyperthermia.

PURPOSE: IFN-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) has been described as an antiangiogenic chemokine and displays a potent antitumor activity in vivo. In the present study, we try to investigate whether the combination therapy of hyperthermia, a physical antiangiogenic modality, with CXCL10 would completely eradicate the established solid tumors. METHODS: Immunocompetent BALB/c mice bearing Meth A fibrosarcoma were established. Mice were treated with either CXCL10 at 25 microg/kg once a day for 20 days, hyperthermia was given twice (at 42 degrees C for 1 h, on day 6 and 12 after the initiation of CXCL10), or together. Tumor volume and survival time were observed. The microvessel density was determined by CD31 immunofluorescence. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues. RESULTS: The results showed that CXCL10 and hyperthermia inhibited the growth of Meth A fibrosarcoma and interestingly, the combination therapy enhanced the antiangiogenic effects and completely eradicated the established solid tumors. Histological examination revealed that CXCL10 + hyperthermia led to increased induction of apoptosis, tumor necrosis, and elevated lymphocyte infiltration compared with the controls. Moreover, the tumor eradicated animals developed a protective T-cell-dependent antitumor memory response against Meth A tumor cells rechallenge. CONCLUSIONS: Our finding is that the combination therapy can achieve a synergistic antitumor efficacy, supporting the idea that the combination of two antiangiogenic agents may lead to improved clinical outcome. These findings could open new perspectives in clinical antitumor therapy.