Ribosomal proteins: the missing piece in the inflammation puzzle?

Ribosomal proteins (RPs) are constituents of macromolecular machinery, ribosome that translates genetic information into proteins. Besides ribosomal functions, RPs are now getting appreciated for their 'moonlighting'/extra-ribosomal functions modulating many cellular processes. Accumulating evidence suggests that a number of RPs are involved in inflammation. Though acute inflammation is a part of the innate immune response, uncontrolled inflammation is a driving factor for several chronic inflammatory diseases. An in-depth understanding of inflammation regulation has always been valued for the better management of associated diseases. Hence, this review first outlines the common livelihood of RPs and then provides a comprehensive account of five RPs that significantly contribute to the inflammation process. Finally, we discuss the possible therapeutic uses of RPs against chronic inflammatory diseases.

Biochanin A impedes STAT3 activation by upregulating p38δ MAPK phosphorylation in IL-6-stimulated macrophages.

OBJECTIVE: IL-6-induced STAT3 activation is associated with various chronic inflammatory diseases. In this study, we investigated the anti-STAT3 mechanism of the dietary polyphenol, biochanin A (BCA), in IL-6-treated macrophages. METHODS: The effect of BCA on STAT3 and p38 MAPK was analyzed by immunoblot. The localization of both these transcription factors was determined by immunofluorescence and fractionation studies. The impact on DNA-binding activity of STAT3 was studied by luciferase assay. To understand which of the isoforms of p38 MAPK was responsible for BCA-mediated regulation of STAT3, overexpression of the proteins, site-directed mutagenesis, pull-down assays and computational analysis were performed. Finally, adhesion-migration assays and semi-quantitative PCR were employed to understand the biological effects of BCA-mediated regulation of STAT3. RESULTS: BCA prevented STAT3 phosphorylation (Tyr705) and increased p38 MAPK phosphorylation (Thr180/Tyr182) in IL-6-stimulated differentiated macrophages. This opposing modulatory effect of BCA was not observed in cells treated with other stress-inducing stimuli that activate p38 MAPK. BCA abrogated IL-6-induced nuclear translocation of phospho-STAT3 and its transcriptional activity, while increasing the cellular abundance of phospho-p38 MAPK. BCA-induced phosphorylation of p38δ, but not α, ß, or γ was responsible for impeding IL-6-induced STAT3 phosphorylation. Interestingly, interaction with phospho-p38δ masked the Tyr705 residue of STAT3, preventing its phosphorylation. BCA significantly reduced STAT3-dependent expression of icam-1 and mcp-1 diminishing IL-6-mediated monocyte adhesion and migration. CONCLUSION: This differential regulation of STAT3 and p38 MAPK in macrophages establishes a novel anti-inflammatory mechanism of BCA which could be important for the prevention of IL-6-associated chronic inflammatory diseases.

Post-transcriptional regulation of C-C motif chemokine ligand 2 expression by ribosomal protein L22 during LPS-mediated inflammation.

Monocyte infiltration to the site of pathogenic invasion is critical for inflammatory response and host defence. However, this process demands precise regulation as uncontrolled migration of monocytes to the site delays resolution of inflammation and ultimately promotes chronic inflammation. C-C motif chemokine ligand 2 (CCL2) plays a key role in monocyte migration, and hence, its expression should be tightly regulated. Here, we report a post-transcriptional regulation of CCL2 involving the large ribosomal subunit protein L22 (RPL22) in LPS-activated, differentiated THP-1 cells. Early events following LPS treatment include transcriptional upregulation of RPL22 and its nuclear accumulation. The protein binds to the first 20 nt sequence of the 5'UTR of ccl2 mRNA. Simultaneous nuclear translocation of up-frameshift-1 protein and its interaction with RPL22 results in cytoplasmic degradation of the ccl2 mRNA at a later stage. Removal of RPL22 from cells results in increased expression of CCL2 in response to LPS causing disproportionate migration of monocytes. We propose that post-transcriptional regulation of CCL2 by RPL22 fine-tunes monocyte infiltration during a pathogenic insult and maintains homeostasis of the immune response critical to resolution of inflammation. DATABASES: Microarray data are available in NCBI GEO database (Accession No GSE126525).

STAT3 and NF-κB are common targets for kaempferol-mediated attenuation of COX-2 expression in IL-6-induced macrophages and carrageenan-induced mouse paw edema.

Cycloxygenase-2 (COX-2) is the inducible isoform of cycloxygenase enzyme family that catalyzes synthesis of inflammatory mediators, prostanoids and prostaglandins, and therefore, can be targeted by anti-inflammatory drugs. Here, we showed a plant polyphenol, kaempferol, attenuated IL-6-induced COX-2 expression in human monocytic THP-1 cells suggesting its beneficial role in chronic inflammation. Kaempferol deactivated and prevented nuclear localization of two major transcription factors STAT3 and NF-κB, mutually responsible for COX-2 induction in response to IL-6. Moreover, STAT3 and NF-κB were simultaneously deactivated by kaempferol in acute inflammation, as shown by carrageenan-induced mouse paw edema model. The concomitant reduction in COX-2 expression in paw tissues suggested kaempferol's role in mitigation of inflammation by targeting STAT3 and NF-κB.

Antiatherogenic Roles of Dietary Flavonoids Chrysin, Quercetin, and Luteolin.

Cardiovascular diseases (CVDs) are the commonest cause of global mortality and morbidity. Atherosclerosis, the fundamental pathological manifestation of CVDs, is a complex process and is poorly managed both in terms of preventive and therapeutic intervention. Aberrant lipid metabolism and chronic inflammation play critical roles in the development of atherosclerosis. These processes can be targeted for effective management of the disease. Although managing lipid metabolism is in the forefront of current therapeutic approaches, controlling inflammation may also prove to be crucial for an efficient treatment regimen of the disease. Flavonoids, the plant-derived polyphenols, are known for their antiinflammatory properties. This review discusses the possible antiatherogenic role of 3 flavonoids, namely, chrysin, quercetin, and luteolin primarily known for their antiinflammatory properties.