MCPIP1 Inhibits Hepatic Stellate Cell Activation in Autocrine and Paracrine Manners, Preventing Liver Fibrosis.

BACKGROUND & AIMS: Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice. In addition, mice with liver-specific deletion of Zc3h12a develop features of primary biliary cholangitis. In this study, we investigated the role of MCPIP1 in liver fibrosis and HSC activation. METHODS: We analyzed MCPIP1 levels in patients' fibrotic livers and hepatic cells isolated from fibrotic murine livers. In vitro experiments were conducted on primary HSCs, cholangiocytes, hepatocytes, and LX-2 cells with MCPIP1 overexpression or silencing. RESULTS: MCPIP1 levels are induced in patients' fibrotic livers compared with their nonfibrotic counterparts. Murine models of fibrosis revealed that its level is increased in HSCs and hepatocytes. Moreover, hepatocytes with Mcpip1 deletion trigger HSC activation via the release of connective tissue growth factor. Overexpression of MCPIP1 in LX-2 cells inhibits their activation through the regulation of TGFB1 expression, and this phenotype is reversed upon MCPIP1 silencing. CONCLUSIONS: We demonstrated that MCPIP1 is induced in human fibrotic livers and regulates the activation of HSCs in both autocrine and paracrine manners. Our results indicate that MCPIP1 could have a potential role in the development of liver fibrosis.

An Atlas of the Hidradenitis Suppurativa Transcriptome.

INTRODUCTIONS: Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin. Both genetic and environmental factors contribute to the risk of developing HS, but the pathogenesis of this disease is currently not fully understood. The aim of this study was to further current understanding of the molecular background of HS with the use of global transcriptome analyses. METHODS: Transcriptome profiling of perilesional and lesional skin of five patients with HS and six healthy control patients was performed by next-generation sequencing. Groups of differentially expressed genes characteristic of the skin of patients with HS were shortlisted by bioinformatic analysis. RESULTS: RNA sequencing followed by bioinformatic profiling revealed profound enrichment of inflammatory-related processes in both lesional and perilesional skin of patients with HS. There were, however, distinct differences in the gene expression profiles between the lesional and perilesional skin, with 1488 genes differentially expressed. Genes encoding typical proinflammatory cytokines were profoundly enriched within HS lesions. In contrast, those encoding mediators of extracellular matrix organization were highly expressed mostly in the perilesional area. CONCLUSIONS: Our study provides novel insights into the mechanisms underlying the pathogenesis of HS, and the results also have potential clinical implications in both diagnosis and therapeutics.

Hepatic Mcpip1 regulates adaptation to food restriction in mice.

Monocyte-chemoattractant protein-induced protein 1 (MCPIP1, or Regnase-1) is an endoribonuclease that degrades translationally active mRNA molecules. MCPIP1 is mostly known for its anti-inflammatory actions, but it is also an important regulator of adipogenesis and lipid metabolism. Its overexpression impairs adipogenesis by reducing mRNA levels of C/EBPß and PPARγ, key transcription factors regulating this process. Although adipocytes overexpressing MCPIP1 are characterised by impaired glucose uptake, the function of MCPIP1 in hepatocyte metabolism remains unknown. In this study, conditional deletion of Zc3h12a in murine liver epithelial cells was used to characterise the role of Mcpip1 in adaptation to 24-hour food restriction. We found that Mcpip1 deficiency in liver epithelial cells (Mcpip1fl/flAlbCre mice) resulted in higher blood glucose levels in response to fasting in comparison to Mcpip1fl/fl counterparts. Hepatic proteome analysis showed 26 down-regulated and 117 up-regulated proteins in Mcpip1fl/flAlbCre animals that were involved in cellular adhesion, extracellular matrix and metabolic processes. In conclusion, our studies provide new insight into the hepatic function of Mcpip1 and its involvement in metabolic control.

MCPIP1 functions as a safeguard of early embryonic development.

Monocyte chemoattractant protein-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase that has been described as a key negative modulator of inflammation. MCPIP1 also controls numerous tumor-related processes, such as proliferation, apoptosis and differentiation. In this study, we utilized a zebrafish model to investigate the role of Mcpip1 during embryogenic development. Our results demonstrated that during embryogenesis, the expression of the zc3h12a gene encoding Mcpip1 undergoes dynamic changes. Its transcript levels gradually increase from the 2-cell stage to the spherical stage and then decrease rapidly. We further found that ectopic overexpression of wild-type Mcpip1 but not the catalytically inactive mutant form resulted in an embryonic lethal phenotype in zebrafish embryos (24 hpf). At the molecular level, transcriptomic profiling revealed extensive changes in the expression of genes encoding proteins important in the endoplasmic reticulum stress response and in protein folding as well as involved in the formation of primary germ layer, mesendoderm and endoderm development, heart morphogenesis and cell migration. Altogether, our results demonstrate that the expression of zc3h12a must be tightly controlled during the first cell divisions of zebrafish embryos and that a rapid decrease in its mRNA expression is an important factor promoting proper embryo development.

Depletion of Mcpip1 in murine myeloid cells results in intestinal dysbiosis followed by allergic inflammation.

MCPIP1 (called also Regnase-1) is a negative regulator of inflammation. Knockout of the Zc3h12a gene, encoding Mcpip1 in cells of myeloid origin (Mcpip1MKO), has a pathological effect on many organs. The aim of this study was to comprehensively analyze pathological changes in the skin caused by Mcpip1 deficiency in phagocytes with an emphasis on its molecular mechanism associated with microbiome dysbiosis. Mcpip1MKO mice exhibited spontaneous wound formation on the skin. On a molecular level, the Th2-type immune response was predominantly characterized by an increase in Il5 and Il13 transcript levels, as well as eosinophil and mast cell infiltration. Irritation by DNFB led to a more severe skin contact allergy in Mcpip1MKO mice. Allergic reactions on the skin were strongly influenced by gut dysbiosis and enhanced systemic dissemination of bacteria. This process was followed by activation of the C/EBP pathway in peripheral macrophages, leading to local changes in the cytokine microenvironment that promoted the Th2 response. A reduced bacterial load inhibited allergic inflammation, indicating the role of intestinal dysbiosis in the development of skin diseases. Our results clearly show that MCPIP1 in phagocytes is an essential negative regulator that controls the gut-skin axis.

Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium.

BACKGROUND AND AIMS: NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. METHODS: In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating ß-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). CONCLUSION: We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.

Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation.

Tyrosine kinase inhibitors (TKIs) are the most commonly used targeted therapeutics in clear-cell renal cell carcinoma (ccRCC); however, drug resistance limits their utility and can lead to tumor "flare-up" and progression. In this study, we show that RCC resistance to sunitinib and sorafenib involves different mechanisms and leads to increased malignancy. Sunitinib decreased tumor growth and cell motility along with increased E-cadherin expression and secretion of the proangiogenic cytokines IL6 and IL8, which activated senescence in ccRCC cells and led to VE-cadherin phosphorylation, enhancing tumor angiogenesis. Sorafenib resistance increased the levels of mesenchymal markers and the secretion of MMP9, which cleaved VE-cadherin and disrupted endothelial cell integrity. Both sunitinib resistance and sorafenib resistance led to activation of the c-Met receptor IRAK1 and downregulation of the tumor suppressor MCPIP1, resulting in an increase in the metastasis of resistant cells, possibly due in part to enhanced vascularization of ccRCC. MCPIP1 overexpression partially overcame resistance to these drugs by decreasing micrometastasis and decreasing the expression of factors involved in tumorigenesis. In tumor samples from ccRCC patients, we observed a significant increase in the level of the c-Met receptor, IRAK1 and a decrease in MCPIP1 with respect to normal kidney tissue. Our results indicate separate novel mechanisms for sunitinib and sorafenib resistance, which both lead to MCPIP1 inhibition and ccRCC progression. The presented study suggests caution in the treatment of RCC with TKIs, which may lead to the unintended outcome of tumor progression.

MCPIP1 regulates focal adhesion kinase and Rho GTPase-dependent migration in clear cell renal cell carcinoma.

Metastasis is responsible for as many as 90% of cancer-associated deaths in patients. The metastatic process is a result of tumor cell migration and invasion associated with morphological changes and increased expression of several genes involved in cell migration. We have already shown that monocyte chemotactic protein-1-induced protein-1 (MCPIP1), a negative regulator of inflammatory processes, influences cell morphology, prevents the epithelial to mesenchymal transition program, and regulates metastasis in clear cell renal cell carcinoma (ccRCC). However, the mechanism by which MCPIP1 influences cell migratory potential is unknown. In this study, we investigated how MCPIP1 affects ccRCC cell migration. We showed that MCPIP1 prevents morphological transformation and drastically reduces the migration of ccRCC cells. MCPIP1 decreases the levels of Rho GTPases and reduces the phosphorylation of FAK at Tyr-397 and Tyr-861 and Src at Tyr-418. The loss of MCPIP1 RNase activity results in actin remodeling, an increase in the levels of Rho proteins and the phosphorylation of FAK on Tyr-397, which leads to Tyr-418 Src phosphorylation and an increase in migration activity. Moreover, we observed increased expression of IL-1ß in ccRCC cells and tumors lacking MCPIP1 RNase activity. Additionally, microarray analysis of tissues from patients with ccRCC revealed changes in the expression of several genes correlated with migration as tumor progression occurred. This study indicates an important role of MCPIP1 as a regulator of migratory potential in ccRCC.

Selected transgenic murine models of human autoimmune liver diseases.

Murine models of human diseases are of outmost importance for both studying molecular mechanisms driving their development and testing new treatment strategies. In this review, we first discuss the etiology and risk factors for autoimmune liver disease, including primary biliary cholangitis, autoimmune hepatitis and primary sclerosing cholangitis. Second, we highlight important features of murine transgenic models that make them useful for basic scientists, drug developers and clinical researchers. Next, a brief description of each disease is followed by the characterization of selected animal models.

Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC. METHODS: We analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis. RESULTS: Skin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-ß). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9. CONCLUSIONS: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.

MCPIP1 inhibits Wnt/ß-catenin signaling pathway activity and modulates epithelial-mesenchymal transition during clear cell renal cell carcinoma progression by targeting miRNAs.

Epithelial-mesenchymal transition (EMT) refers to the acquisition of mesenchymal properties in cells participating in tumor progression. One hallmark of EMT is the increased level of active ß-catenin, which can trigger the transcription of Wnt-specific genes responsible for the control of cell fate. We investigated how Monocyte Chemotactic Protein-1-Induced Protein-1 (MCPIP1), a negative regulator of inflammatory processes, affects EMT in a clear cell renal cell carcinoma (ccRCC) cell line, patient tumor tissues and a xenotransplant model. We showed that MCPIP1 degrades miRNAs via its RNase activity and thus protects the mRNA transcripts of negative regulators of the Wnt/ß-catenin pathway from degradation, which in turn prevents EMT. Mechanistically, the loss of MCPIP1 RNase activity led to the upregulation of miRNA-519a-3p, miRNA-519b-3p, and miRNA-520c-3p, which inhibited the expression of Wnt pathway inhibitors (SFRP4, KREMEN1, CXXC4, CSNK1A1 and ZNFR3). Thus, the level of active nuclear ß-catenin was increased, leading to increased levels of EMT inducers (SNAI1, SNAI2, ZEB1 and TWIST) and, consequently, decreased expression of E-cadherin, increased expression of mesenchymal markers, and acquisition of the mesenchymal phenotype. This study revealed that MCPIP1 may act as a tumor suppressor that prevents EMT by stabilizing Wnt inhibitors and decreasing the levels of active ß-catenin and EMT inducers.

MCPIP1/Regnase-1 Expression in Keratinocytes of Patients with Hidradenitis Suppurativa: Preliminary Results.

The pathogenesis of hidradenitis suppurativa (HS) is yet to be fully understood. However, inflammation is a key element in the development of skin lesions. The aim of this study was to evaluate the expression of monocyte chemotactic protein-1-induced protein-1 (MCPIP1) in the skin of patients suffering from HS. Skin biopsies of 15 patients with HS and 15 healthy controls were obtained and processed for immunohistochemistry, western blot, and real time PCR. The highest mean MCPIP1 mRNA expression was found in the inflammatory lesional skin of HS patients. It was significantly higher than MCPIP1 mRNA expression in the biopsies from both healthy controls and non-lesional skin of HS patients. Western blot analysis indicated that expression of MCPIP1 was elevated within both lesional and non-lesional skin compared to the healthy control. The increased MCPIP1 mRNA and protein expression level in HS lesions may indicate its possible role in the disease pathogenesis.

Subversion of Lipopolysaccharide Signaling in Gingival Keratinocytes via MCPIP-1 Degradation as a Novel Pathogenic Strategy of Inflammophilic Pathobionts.

Periodontal disease (PD) is an inflammatory disease of the supporting tissues of the teeth that develops in response to formation of a dysbiotic biofilm on the subgingival tooth surface. Although exacerbated inflammation leads to alveolar bone destruction and may cause tooth loss, the molecular basis of PD initiation and progression remains elusive. Control over the inflammatory reaction and return to homeostasis can be efficiently restored by negative regulators of Toll-like receptor (TLR) signaling pathways such as monocyte chemoattractant protein-induced protein 1 (MCPIP-1), which is constitutively expressed in gingival keratinocytes and prevents hyperresponsiveness in the gingiva. Here, we found that inflammophilic periodontal species influence the stability of MCPIP-1, leading to an aggravated response of the epithelium to proinflammatory stimulation. Among enzymes secreted by periodontal species, gingipains-cysteine proteases from Porphyromonas gingivalis-are considered major contributors to the pathogenic potential of bacteria, strongly influencing the components of the innate and adaptive immune system. Gingipain proteolytic activity leads to a rapid degradation of MCPIP-1, exacerbating the inflammatory response induced by endotoxin. Collectively, these results establish a novel mechanism of corruption of inflammatory signaling by periodontal pathogens, indicating new possibilities for treatment of this chronic disease. IMPORTANCE Periodontitis is a highly prevalent disease caused by accumulation of a bacterial biofilm. Periodontal pathogens use a number of virulence strategies that are under intensive study to find optimal therapeutic approaches against bone loss. In our work, we present a novel mechanism utilized by the key periodontal pathogen Porphyromonas gingivalis, based on the selective degradation of the negative regulator of inflammation, MCPIP-1. We found that the diminished levels of MCPIP-1 in gingival keratinocytes-cells at the forefront of the fight against bacteria-cause sensitization to endotoxins produced by other oral species. This results in an enhanced inflammatory response, which promotes the growth of inflammophilic pathobionts and damage of tooth-supporting tissues. Our observation is relevant to understanding the molecular basis of periodontitis and the development of new methods for treatment.

Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts.

Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated that MCPIP1 regulates lipid metabolism both in adipose tissue and in hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of nonalcoholic fatty liver disease (NAFLD). We used control Mcpip1fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/fl LysMCre ) and in hepatocytes (Mcpip1fl/fl AlbCre ), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/fl LysMCre mice fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in low plasma glucose level and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma and high Tnfa, Il6, IL1b mRNA levels in the liver and brown adipose tissue (BAT). Proinflammatory leukocyte infiltration into BAT, together with low expression of Ucp1 and Ppargc1a, resulted in hypothermia of 22-week-old Mcpip1fl/fl LysMCre mice. On the other hand, there were no significant changes in phenotype in Mcpip1fl/fl AlbCre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and ß-oxidation in these mice, they remained asymptomatic. Upon feeding with a HFD, Mcpip1fl/fl LysMCre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by low plasma glucose level and dyslipidemia, along with proinflammatory phenotype. Mcpip1fl/fl AlbCre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected. We have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.

MCPIP-1 Restricts Inflammation via Promoting Apoptosis of Neutrophils.

Monocyte chemoattractant protein-induced protein-1 (MCPIP-1) is a potent inhibitor of inflammatory response to pathogens. Acting as endonuclease against transcripts of inflammatory cytokines or transcription factors MCPIP-1 can significantly reduce the cytokine storm, thus limiting the tissue damage. As the adequate resolution of inflammation depends also on the efficient clearance of accumulated neutrophils, we focused on the role of MCPIP-1 in apoptosis and retention of neutrophils. We used peritoneal neutrophils from cell-specific MCPIP-1 knockout mice and showed prolonged survival of these cells. Moreover, we confirmed that MCPIP-1-dependent degradation of transcripts of antiapoptotic genes, including BCL3, BCL2A1, BCL2L1, and for the first time MCL-1, serves as an early event in spontaneous apoptosis of primary neutrophils. Additionally, we identified previously unknown miRNAs as potential binding partners to the MCPIP-1 transcript and their regulation suggest a role in MCPIP-1 half-life and translation. These phenomena may play a role as a molecular switch that balances the MCPIP-1-dependent apoptosis. Besides that, we determined these particular miRNAs as integral components of the GM-CSF-MCPIP-1 axis. Taken together, we identified the novel anti-inflammatory role of MCPIP-1 as a regulator of accumulation and survival of neutrophils that simultaneously promotes an adequate resolution of inflammation.

Fatty Acids and a High-Fat Diet Induce Epithelial-Mesenchymal Transition by Activating TGFß and ß-Catenin in Liver Cells.

Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial-mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFß), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFß, MMP9, and ß-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFß and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype.

Deletion of Mcpip1 in Mcpip1fl/flAlbCre mice recapitulates the phenotype of human primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC in 6-52-week-old mice. We found that Mcpip1 deficiency in the liver (Mcpip1fl/flAlbCre) recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1fl/flLysMCre mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1fl/flAlbCre livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1fl/flAlbCre mice was robust in 6-week-old, but milder in 12-24-week-old mice. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1fl/flAlbCre mice showed 812 and 8 differentially expressed genes, respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. In conclusion, Mcpip1fl/flAlbCre mice display early postnatal phenotype that recapitulates most of the features of human PBC.

MCPIP1 RNase and Its Multifaceted Role.

Inflammation is an organism's physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation is regulated at many levels, and one of these levels is post-transcriptional regulation, which controls the half-life of transcripts that encode inflammatory mediators. One of the proteins responsible for controlling the amount of mRNA in a cell is the RNase monocyte chemoattractant protein-induced protein 1 (MCPIP1). The studies conducted so far have shown that MCPIP1 is involved not only in the regulation of inflammation but also in many other physiological and pathological processes. This paper provides a summary of the information on the role of MCPIP1 in adipogenesis, angiogenesis, cell differentiation, cancer, and skin inflammation obtained to date.