Elevated Expression Of Pro-inflammatory Cytokines Research Articles

Regulation of dendritic cell survival and cytokine production by osteoprotegerin

The TNF family ligand, RANKL, and its two TNFR family receptors, RANK and OPG, enable coordinated regulation between the skeletal and immune systems. Relatively little is known about how OPG influences RANKL-RANK interactions for the regulation of DCs. Here, we show that OPG KO bone marrow-derived DCs survive better and produce more TNF-alpha, IL-12p40, and IL-23 in response to Escherichia coli LPS than WT DCs. RANKL is induced on DCs within 24 h after LPS stimulation. OPG limits RANKL-RANK interactions between DCs, which can promote DC survival and elevated expression of proinflammatory cytokines. Survival of and cytokine production by OPG KO DCs are inhibited by soluble OPG; conversely, anti-OPG enhances survival and cytokine production by WT DCs. Bim KO DCs, like OPG KO, also survive longer and produce more TNF-alpha than WT DCs; however, unlike OPG KO, Bim KO DCs do not produce more IL-23. In addition, after inoculation with LPS, OPG KO mice produce more TNF-alpha and IL-12p40 than WT mice but not more IL-6. Thus, OPG regulates not only DC survival but also the nature of DC-dependent inflammatory responses.

Nramp1 expression by dendritic cells modulates inflammatory responses during Salmonella Typhimurium infection.

Host resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) is mediated by natural resistance-associated macrophage protein 1 (Nramp1/Slc11a1). Nramp1 is critical to host defence, as mice lacking Nramp1 fail to control bacterial replication and succumb to low doses of S. Typhimurium. Despite this crucial role, the mechanisms underlying Nramp1's protective effects are unclear. Dendritic cells (DCs) that sample the intestinal lumen are among the first cells encountered by S. Typhimurium following oral infection and act as a conduit for S. Typhimurium to cross the intestinal epithelial barrier. We report that DCs, including intestinal, splenic and bone marrow-derived DCs (BMDCs), express Nramp1 protein. In the small intestine, Nramp1 expression is greater in a subset of DCs (CD11c(+)CD103(-)) characterized by the elevated expression of pro-inflammatory cytokines in response to bacterial products. While Nramp1 expression did not affect S. Typhimurium replication in BMDCs, infected Nramp1+/+ BMDCs and intestinal CD11c(+)CD103(-) DCs secreted more inflammatory cytokines (IL-6, IL-12 and TNF-alpha) than Nramp1-/-, suggesting that Nramp1 expression may promote a more rapid inflammatory response following infection. Collectively, these findings reveal a new role for DCs and Nramp1 in modulating the host inflammatory response to S. Typhimurium.

Metabolomics Reveals that Hepatic Stearoyl-CoA Desaturase 1 Downregulation Exacerbates Inflammation and Acute Colitis

To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases.

Could inflammation be a key component in the progression of benign prostatic hyperplasia?

This review covers recent developments in the role of chronic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). A paper on the subanalysis of the Medical Therapy of Prostate Symptoms study highlighted the role of chronic inflammation in the progression of BPH as determined by the pathological tissue obtained in the 4.5-year study. It shows patients with inflammation had significantly larger prostates, higher serum prostate specific antigen and a greater risk of urinary retention. This follows several other in-situ studies which demonstrated that elevated expression of pro-inflammatory cytokines in BPH. IL-6, IL-8 and IL-17 may perpetuate chronic immune response in BPH and induce fibromuscular growth by an autocrine or paracrine loop or via induction of COX-2 expression. Immune reaction may be activated via Toll-like receptor signalling and mediated by macrophages and T cells. Conversely, anti-inflammatory factors such as macrophage inhibitory cytokine-1 decreased in symptomatic BPH tissues. Animal models provided evidence for the presence of unique T-cell subsets which may suppress autoimmunity in healthy Sprague-Dawley rats resistant to chronic nonbacterial prostatitis. The pathogenesis of BPH is still unresolved, although chronic inflammation may play a significant role in disease progression. Further research is required to determine the putative (auto)antigen, the influence of infiltrating inflammatory cells on the stromal/epithelial cell crosstalk and a new classification of BPH quantifying local and systemic inflammatory/immune reactions in relation to clinical relevance. New treatments for BPH investigating these specific inflammatory pathways may arise as we learn more about the way they work.

Twist Regulates Cytokine Gene Expression through a Negative Feedback Loop that Represses NF-κB Activity

During Drosophila embryogenesis, the dorsal transcription factor activates the expression of twist, a transcription factor required for mesoderm formation. We show here that the mammalian twist proteins, twist-1 and -2, are induced by a cytokine signaling pathway that requires the dorsal-related protein RelA, a member of the NF-κB family of transcription factors. Twist-1 and -2 repress cytokine gene expression through interaction with RelA. Mice homozygous for a twist-2 null allele or doubly heterozygous for twist-1 and -2 alleles show elevated expression of proinflammatory cytokines, resulting in perinatal death from cachexia. These findings reveal an evolutionarily conserved signaling circuit in which twist proteins regulate cytokine signaling by establishing a negative feedback loop that represses the NF-κB-dependent cytokine pathway.