Deficiency of interleukin-19 exacerbates acute lung injury induced by intratracheal treatment of hydrochloric acid.

Interleukin (IL-19) belongs to the IL-10 family of cytokines and plays diverse roles in inflammation, cell development, viral responses, and lipid metabolism. Acute lung injury (ALI) is a severe respiratory condition associated with various diseases, including severe pneumonia, sepsis, and trauma, lacking established treatments. However, the role of IL-19 in acute inflammation of the lungs is unknown. We reported the impact of IL-19 functional deficiency in mice crossed with an ALI model using HCl. Lungs damages, neutrophil infiltration, and pulmonary edema induced by HCl were significantly worse in IL-19 knockout (KO) mice than in wild-type (WT) mice. mRNA expression levels of C-X-C motif chemokine ligand 1 (CXCL1) and IL-6 in the lungs were significantly higher in IL-19 KO mice than in WT mice. Little apoptosis was detected in lung injury in WT mice, whereas apoptosis was observed in exacerbated area of lung injury in IL-19 KO mice. These results are the first to show that IL-19 is involved in acute inflammation of the lungs, suggesting a novel molecular mechanism in acute respiratory failures. If it can be shown that neutrophils have IL-19 receptors and that IL-19 acts directly on them, it would be a novel drug target.

L-arginine-induced pancreatitis aggravated by inhibiting Na+/Ca2+ exchanger 1.

Na+/Ca2+ exchangers (NCX) are an exchange transporter of Na+ and Ca2+ ions on the plasma membrane. There are three types of NCX: NCX1, NCX2, and NCX3. We have been working for many years to understand the role of NCX1 and NCX2 in gastrointestinal motility. In this study, we focused on the pancreas, an organ closely related to the gastrointestinal tract, and used a mouse model of acute pancreatitis to investigate a possible role for NCX1 in the pathogenesis of pancreatitis. We characterized a model of acute pancreatitis induced by excessive doses of L-arginine. We administered the NCX1 inhibitor SEA0400 (1 mg/kg) 1 hr prior to L-arginine-induced pancreatitis and evaluated pathological changes. Mice treated with NCX1 inhibitors show exacerbation of the disease with decreased survival and increased amylase activity in response to L-arginine-induced experimental acute pancreatitis, and this exacerbation correlates with increased autophagy mediated by LC3B and p62. These results suggest that NCX1 has a role in regulating pancreatic inflammation and acinar cell homeostasis.

Interleukin-19 Gene-Deficient Mice Promote Liver Fibrosis via Enhanced TGF-ß Signaling, and the Interleukin-19-CCL2 Axis Is Important in the Direction of Liver Fibrosis.

IL-19 is a cytokine discovered by homologous searching with IL-10 and is produced by non-immune cells, such as keratinocytes, in addition to immune cells, such as macrophages. Liver fibrosis results from the inflammation and activation of hepatic stellate cells via chronic liver injury. However, the participation of IL-19 in liver fibrosis remains to be sufficiently elucidated. Our group studied the immunological function of IL-19 in a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. IL-19 gene-deficient (KO) mice and body weight-matched wild-type (WT) mice were used. A liver fibrosis mouse model was created via CCl4 administration (two times per week) for 8 weeks. In CCl4-induced liver fibrosis, serum analysis revealed that IL-19 KO mice had higher ALT levels compared to WT mice. IL-19 KO mice had worse fibrosis, as assessed by morphological evaluation of total area stained positive with Azan and Masson trichrome. In addition, the expression of α-SMA was increased in liver tissues of IL-19 KO mice compared to WT mice. Furthermore, mRNA expression levels of TGF-ß and α-SMA were enhanced in IL-19 KO mice compared to WT mice. In vitro assays revealed that IL-19-high expressing RAW264.7 cells inhibited the migration of NIH3T3 cells via the inhibited expression of CCL2 in the presence of CCl4 and IL-4. These findings indicate that IL-19 plays a critical role in liver fibrosis by affecting TGF-ß signaling and the migration of hepatic stellate cells during liver injury. Enhancement of the IL-19 signaling pathway is a potential treatment for liver fibrosis.

Functional role of IL-19 in a mouse model of L-arginine-induced pancreatitis and related lung injury.

IL-19 is a member of IL-10 family and is mainly produced by macrophages. Acute pancreatitis (AP) is an inflammatory disease characterized by acinar cell injury and necrosis. In the present study, the role of IL-19 in AP and AP-associated lung injury in mice was explored using L-arginine-induced pancreatitis. Experimental pancreatitis was induced by intraperitoneal injection of L-arginine in wild-type (WT) and IL-19 gene deficient (IL-19 KO) mice. In L-arginine treated mice, the serum amylase level was significantly increased in IL-19 KO mice, and interstitial edema, analyzed using hematoxylin and eosin (H&E)-stained sections, was aggravated mildly in IL-19 KO mice compared to WT mice. Compared to WT mice treated with L-arginine, mRNA expression of tumor necrosis factor (TNF)-α was significantly upregulated in IL-19 KO mice treated with L-arginine. In WT mice, IL-19 mRNA was equally expressed in the pancreas of both control and L-arginine treated mice. The condition of lung alveoli in WT and IL-19 KO mice treated with L-arginine was then evaluated. In mice with L-arginine-induced pancreatitis, alveolar area was remarkedly decreased, and expression of lung myeloperoxidase was significantly increased in IL-19 KO mice compared to WT mice. In the lungs, mRNA expressions of IL-6 and inducible nitric oxide synthase were significantly increased in IL-19 KO mice compared to WT mice. In summary, IL-19 was proposed to alleviate L-arginine-induced pancreatitis by regulating TNF-α production and to protect against AP-related lung injury by inhibiting neutrophil migration.

[Recent topics on interorgan communication networks and gut microbiota].

The living body is composed of diverse organ systems, each of which has its own characteristic control mechanisms and complex in vivo responses. Between the brain and organs such as the heart, kidney, liver, pancreas, gastrointestinal tract, and even muscles, there is a sophisticated and complex regulatory system. Coordinated interactions through communication between organs are essential for maintaining health. In this review, we introduce four research trends in inter-organ networks, with a focus on the digestive system: 1) Inter-organ networks on metabolic systems, 2) Inter-organ networks originating from the gastrointestinal tract, 3) Intestinal bacteria, that is one of the biggest topics in recent years, 4) Research results on the involvement of gut microbiota in the inter-organ network between the kidney and the gastrointestinal tract. An integrated understanding and investigation of the regulatory mechanisms of inter-organ communication networks are expected to extend healthy life span and improve quality of life.

Stress decreases contraction of the colon, and the effects of stress are different among the regions of the colon.

Stress affects a variety of organs. Diarrhea and constipation are closely related to stress, which involves the gastrointestinal motility of the colon. We compared the gastrointestinal motility of the proximal, mid, and distal colon in mice with stress. Stress was applied by water immersion restraint. Colon motility was measured using an isotonic transducer in the direction of the circular muscles. Electric field stimulation-induced contractions in stressed mice were reduced compared to control mice in the proximal and distal colon. On the other hand, in the mid colon, contraction in control mice and stressed mice were almost same. This interesting difference between the regions may provide a clue to the functional abnormalities in gastrointestinal motility associated with stress.

[Therapeutic application utilizing the anti-inflammatory effect of IL-19].

Interleukin-19 (IL-19) is a member of the IL-10 family and is an anti-inflammatory cytokine produced mainly by macrophages, epithelial cells, and vascular smooth muscle cells. In addition, receptors for IL-19, IL-20 receptor 1 and IL-20 receptor 2, are also expressed in the cells mentioned above. The last 10 years from the finding of IL-19, investigations underline the anti-inflammatory role of IL-19 in the human diseases such as psoriasis, asthma, arteriosclerosis, and inflammatory bowel disease. If it is a pro-inflammatory cytokine, therapeutic applications may include the use of neutralizing antibodies, however, because IL-19 exhibits anti-inflammatory effects, recombinant products may be useful in therapeutic applications. However, the therapeutic applications of IL-19 for human disease have not yet been developed. In this review, we present the new findings on the preventive and therapeutic effects of IL-19 on various mouse disease models. Increasing knowledge about mouse disease models will increase the feasibility of future human disease applications.