Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Effects of post-weaning supplementation of immunomodulatory feed ingredient on circulating cytokines and microbial populations in programmed fed beef heifers

The objective was to determine the effects of an immunomodulatory feed ingredient following weaning on cytokine expression and fecal microbial populations of heifers. Commercial Angus heifers (n = 72) were weaned (227 ± 7 d of age), blocked by BW (n = 9 blocks) and randomly assigned to one of 2 pens per block. Pens within weight block (4 heifers/pen) were then randomly assigned to treatments. Heifers were fed twice daily from d 0-60 (to gain 0.75kg/day) and top-dressed with either 18g/heifer/d of the immunomodulatory feed ingredient (Celmanax; Arm and Hammer Animal Nutrition, Princeton, NJ, USA; CEL) or corn-germ meal (CON). Blood samples were collected on d 0, 15, 30, 45, 60 and fecal grab samples on d 0 of the feeding trial. After d 60, two heifers per pen (n=32) were randomly selected for a transportation challenge. Serum samples were collected at h 0, 4, 8, 12 and fecal grab samples at h -24, 0, 24 and 7d post-challenge. Blood samples were analyzed for interferonγ (IFNγ), interleukin-8 (IL-8), and haptoglobin (HP) using commercially available ELISA kits and qRT-PCR for genes of interest associated with cytokine expression. Fecal samples were enumerated for Clostridia and E. coli using selective media (≤ 5 isolates from each media/sample), tested to determine if they were C. perfringens or pathogenic E. coli, and then enriched for detection of Salmonella. Data was analyzed via ANOVA. During the feeding trial, HP was reduced (P = 0.018) in CEL compared to CON at d 15, 45, and 60, while IFNγ and IL-8 did not differ (P > 0.080) between treatments. All cytokines were decreased (P < 0.001) in CEL compared to CON during the challenge. During the feeding trial, HP mRNA was increased (P = 0.045) in CEL compared to CON at d 30 and 60. Similarly, IFNγ mRNA was increased (P = 0.040) in CEL compared to CON, however, other genes of interest did not differ (P > 0.172). Both C. perfringens and total E. coli counts were decreased (P = 0.036) in CEL compared to CON at 24h after the start of the transportation challenge. Clostridia and pathogenic E. coli counts did not differ (P = 0.941) between treatments. Total Clostridia and E. coli counts were increased (P < 0.014) 24h post-challenge. All microbial populations, except pathogenic E. coli, observed decreased (P ≤ 0.009) counts from 24h to 7d post-challenge. Overall, Celmanax supplementation decreased circulating cytokines, and altered microbial populations and gene expression, thus, may serve a role in preparing animals to better cope with immunological challenges.

Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

Cytokine storm is a phenomenon characterized by strong elevated circulating cytokines that most often occur after an overreactive immune system is activated by an acute systemic infection. A variety of cells participate in cytokine storm induction and progression, with profiles of cytokines released during cytokine storm varying from disease to disease. This review focuses on pathophysiological mechanisms underlying cytokine storm induction and progression induced by pathogenic invasive infectious diseases. Strategies for targeted treatment of various types of infection-induced cytokine storms are described from both host and pathogen perspectives. In summary, current studies indicate that cytokine storm-targeted therapies can effectively alleviate tissue damage while promoting the clearance of invading pathogens. Based on this premise, “multi-omics” immune system profiling should facilitate the development of more effective therapeutic strategies to alleviate cytokine storms caused by various diseases.

Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep

Background Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Methods Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology. Results LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. Conclusion IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.