IL-22BP controls the progression of liver metastasis in colorectal cancer

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. // Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. // Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. // Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferator-activated receptor γ coactivators 1 (PGC-1s) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that, in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-κB) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications

Early Post-traumatic Seizure Occurrence in Pediatric Patients Receiving Levetiracetam Prophylaxis With Severe Traumatic Brain Injury

OBJECTIVE Although levetiracetam is used for the prevention of early Post-traumatic seizures (EPTS) after traumatic brain injury (TBI), limited data exist describing the incidence of seizures in pediatric patients receiving levetiracetam prophylaxis. The objective of this research is to evaluate the prevalence of EPTS in children given prophylactic levetiracetam after severe TBI. METHODS This study was conducted at a Level 1 pediatric trauma center and included pediatric patients with severe TBI who received levetiracetam for EPTS prophylaxis. Demographics and clinical information were retrospectively collected and evaluated. The primary outcome was prevalence of clinical or electrographic seizures within 7 days of initial injury as noted in the EMR. RESULTS In 4 of 44 patients (9%), seizures developed despite levetiracetam prophylaxis. Concurrent use of other medications with antiepileptic properties was common (91%). There were no differences in demographic or baseline clinical characteristics between the group of patients experiencing seizures and those who did not. However, craniotomy was significantly more common in the seizure group (75% vs. 18%, p = 0.03). CONCLUSIONS Children receiving prophylaxis with levetiracetam after severe TBI had a lower incidence of seizures (9%) than had previously been reported in the literature (18%). Given the limited literature available supporting the use of levetiracetam for the prevention of EPTS in children experiencing severe TBI, further study is needed to support routine use.</jats:p