In this study, we uncovered the novel mechanism of IL-1α-mediated DRA (SLC26A3) downregulation in the context of Brachyspira spp. induced malabsorptive diarrhea. Experimentally infected pigs with Brachyspira spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either Brachyspira lysate or IL-1α. Both p38 and MK-2 showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. Additionally, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signalling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from Brachyspira lysate, suggesting a minor contribution from another pathway. Together this demonstrates that Brachyspira activates p38 MAPK signalling driving IL-1α expression which activates IL-1R1 causing DRA downregulation. While also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion we elucidated a major pathway involved in DRA downregulation and its role in Brachyspira induced diarrhea. Additionally these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1 β axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra - a recombinant human IL-1 receptor antagonist - and rilonacept - an IL-1 α /IL-1 β trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1 β pathway blockade.

Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

BACKGROUND: Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored.
METHODS: Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro.
RESULTS: We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage.
CONCLUSIONS: Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.

With the declining birth rates and aging societies in developed countries, the average age of the working population is increasing. Older people tend to get tired more easily, so prevention of fatigue is important to improve the quality of life for older workers. This study aimed to assess the mechanism of fatigue in older people, especially focused on relation between dysfunction of erythrocyte and fatigue. Total power (TP), which is the value of autonomic nerve activity, was measured as a value of fatigue and significantly decreased in workers with aging. As properties of senescent erythrocytes, the erythrocyte sedimentation rate and damaged erythrocytes population increased with aging and correlated with TP. These results suggested that the accumulation of damaged erythrocytes contributes to fatigue. Recent studies revealed that senescence-associated secretory phenotype (SASP), a phenomenon in which senescent cells secrete a variety of cytokines, affected hematopoiesis in bone marrow. We analyzed the effects of SASP factors on erythropoiesis and found that Interleukin -1α (IL-1α) suppressed erythrocyte differentiation of hematopoietic stem cells in vitro. We also showed that IL-1α levels in human blood and saliva increase with aging, suggesting the possibility that IL-1α level in saliva can be used to predict the decline in hematopoietic function.

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Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer\'s, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC50 = 17.67 ± 0.89 μM), with a 4-fold increased activity relative to the standard drug indomethacin (IC50 = 67.16 ± 0.17 μM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.

OBJECTIVE: Human β-defensin 1 (hBD-1) is a antimicrobial peptide that is constantly secreted by oral tissues. Hangeshashinto (HST), a traditional Japanese medicine, has been reported to be effective against stomatitis. This study aimed to clarify the profile of HST by comparing the system of production of interleukin-1α (IL-1α) and hBD-1 in human oral mucosal epithelial cells with dexamethasone (DEX), a steroid used for the treatment of stomatitis.
METHODS: Human oral keratinocytes (HOK) were treated with HST, DEX, or HST components (baicalein, baicalin, berberine, and glycyrrhizin) for 24 h, and subsequently cultured for 24 h with or without Pam3CSK4 or lipopolysaccharide (LPS). The cell supernatants, total RNA, and intracellular proteins were collected, and changes in IL-1α and hBD-1 protein production and gene expression were evaluated using ELISA and RT-PCR. The phosphorylation of NF-kB and the cell proliferative ability of HOK were evaluated by western blotting and XTT assay, respectively.
RESULTS: DEX (0.01-10 μM) significantly suppressed IL-1α and hBD-1 production induced by either Pam3CSK4 or LPS, and also decreased cell growth. In contrast, HST inhibited Pam3CSK4- and LPS-induced IL-1α production at a concentration range of 12.5-100 μg/mL without affecting the cell proliferative capacity and hBD-1 production of HOK. Baicalein and baicalin, which are flavonoid ingredients of HST, showed anti-IL-1α production.
CONCLUSIONS: HST may be useful as a therapeutic agent for stomatitis and other inflammatory diseases of the oral cavity.

Bile acids are amphipathic molecules that are synthesized from cholesterol in the liver and facilitate intestinal absorption of lipids and nutrients. They are released into the small intestine upon ingestion of a meal where intestinal bacteria can modify primary into secondary bile acids. Bile acids are cytotoxic at high concentrations and have been associated with inflammatory diseases such as liver inflammation and Barrett\'s Oesophagus. Although bile acids induce pro-inflammatory signalling, their role in inducing innate immune cytokines and inflammation has not been fully explored to date. Here we demonstrate that the bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) induce IL-1α and IL-1β secretion in vitro in primed bone marrow derived dendritic cells (BMDCs). The secretion of IL-1β was found not to require expression of NLRP3, ASC or caspase-1 activity; we can\'t rule out all inflammasomes. Furthermore, DCA and CDCA were shown to induce the recruitment of neutrophils and monocytes to the site of injection an intraperitoneal model of inflammation. This study further underlines a mechanistic role for bile acids in the pathogenesis of inflammatory diseases through stimulating the production of pro-inflammatory cytokines and recruitment of innate immune cells.

Tumor-associated macrophages (TAMs), one of the major components of the tumor microenvironment, contribute to the progression of esophageal squamous cell carcinoma (ESCC). We previously established a direct co-culture system of human ESCC cells and macrophages and reported the promotion of malignant phenotypes, such as survival, growth, and migration, in ESCC cells. These findings suggested that direct interactions between cancer cells and macrophages contribute to the malignancy of ESCC, but its underlying mechanisms remain unclear. In this study, we compared the expression levels of the interferon-induced genes between mono- and co-cultured ESCC cells using a cDNA microarray and found that interferon-inducible protein 16 (IFI16) was most significantly upregulated in co-cultured ESCC cells. IFI16 knockdown suppressed malignant phenotypes and also decreased the secretion of interleukin-1α (IL-1α) from ESCC cells. Additionally, recombinant IL-1α enhanced malignant phenotypes of ESCC cells through the Erk and NF-κB signaling. Immunohistochemistry revealed that high IFI16 expression in human ESCC tissues tended to be associated with disease-free survival and was significantly associated with tumor depth, lymph node metastasis, and macrophage infiltration. The results of this study reveal that IFI16 is involved in ESCC progression via IL-1α and imply the potential of IFI16 as a novel prognostic factor for ESCC.