Induction of Lithostathine/regmRNA Expression by Serum from Rats with Acute Pancreatitis and Cytokines in Pancreatic Acinar AR-42J Cells

doi:10.1006/abbi.1996.0234

Archives of Biochemistry and Biophysics

Volume 330, Issue 1, 1 June 1996, Pages 129-132

https://doi.org/10.1006/abbi.1996.0234 Get rights and content

Abstract

During the acute phase of pancreatitis, expression of most pancreatic enzymes decreases, whereas mRNAs of pancreatitis associated protein and lithostathine/regincrease dramatically. In the present study we have investigated the effect of serum from rats with acute pancreatitis (SAP) and cytokines on the lithostathine/regmRNA expression in AR-42J cells. Lithostathine/regmRNA was strongly induced by SAP in a dose-dependent manner. Induction was abolished by preheating the SAP or by treating the cells with cycloheximide. Treatment with interleukins (IL) IL-1 or IL-6 or dexamethasone alone was ineffective. Combination of IL-1 with IL-6 was also ineffective. Combination of IL-6 with dexamethasone resulted in strong induction of the lithostathine/reggene, but the further addition of IL-1 to the mixture reduced induction. Treatment with tumor necrosis factor-α (TNFα) or interferon-γ (IFNγ) induced lithostathine/regmRNA expression. Combination of dexamethasone with TNFα or IFNγ showed an inhibitory effect on lithostathine/regmRNA expression. These findings suggest that expression of the lithostathine/regmRNA during acute pancreatitis could be mediated by specific combinations of cytokines and/or glucocorticoids.

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Cited by (56)

Development and application of a novel aldehyde nanoparticle-based amplified luminescent proximity homogeneous assay for rapid quantitation of pancreatic stone protein
2022, Clinica Chimica Acta
Citation Excerpt :
Therefore, the finding indicated that the newly developed method might be utilized to determine PSP in human plasma in clinical setting. When the body is infected with bacteria or sepsis, immune cells release pro-inflammatory cytokines such as interleukins-1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon-γ, and the abovementioned cytokines can induce the pancreas to secrete PSP stressfully [35–37]. On the one hand, the released PSP can stimulate bacterial aggregation and participate in host’s response to pathogens through its C-type lectin domain.
Timely diagnosis of bacterial infections is important to prevent sepsis. Classical infection biomarkers have some flaws, and common detection methods are time-consuming. Thus, we aimed to establish an efficient detection method that precisely detects pancreatic stone protein (PSP) in human plasma for the timely diagnosis of bacterial infections.
Based on the novel amplified luminescent proximity homogeneous assay (AlphaLISA) method, donor and acceptor beads modified with aldehyde groups were directly coupled to the anti-PSP antibodies. PSP was quickly detected by a double-antibody sandwich method. Plasma samples from healthy individuals, bacterially infected patients, and acute-phase response patients were tested.
The detection time of the developed method is only 5 min. The results of PSP-AlphaLISA and time-resolved fluorescence were consistent (ρ = 0.9722). The plasma PSP levels of patients with bacterial infection were significantly higher than those of acute-phase response patients and healthy individuals (P < 0.05). PSP levels in patients with bacterial infection with sepsis were significantly higher than those in patients with bacterial infection without sepsis (P < 0.05).
The PSP-AlphaLISA exhibited excellent performance and may be applied to the differential diagnosis between bacterial infection and sepsis in patients without interference from patients with acute-phase response.
Transcriptional activation of Reg2 and Reg3β genes by glucocorticoids and interleukin-6 in pancreatic acinar and islet cells
2013, Molecular and Cellular Endocrinology
Citation Excerpt :
To dissect individual contributions to the promoter activation, we treated cells with single components and in combination. As shown in Fig. 2B, Reg2 promoter was activated 6-fold by DEX alone but not by IL-6 or nicotinamide, which was in contrast to the inhibition of Reg1 gene by glucocorticoids (Dusetti et al., 1996). The addition of IL-6 to DEX did not cause further increase; the addition of nicotinamide to DEX/IL-6 caused a diminished activation.
Reg family proteins are expressed in the pancreas and involved in pancreatitis and islet β-cell growth. In order to explore transcriptional control, we transfected luciferase reporter genes driven by Reg promoters into acinar AR42J and islet MIN6 cells. Dexamethasone (DEX) significantly increased the promoter expression of Reg2 and Reg3β genes and the levels of endogenous Reg3β mRNA and protein in AR42J cells. DEX-induced promoter activation was inhibited by the inhibitor of poly(ADP-ribose) polymerase, nicotinamide. In MIN6 cells, DEX moderately stimulated the transcription of Reg3β but not Reg2 promoter. While IL-6 alone had no effect, coculture with DEX produced a remarkable synergism on Reg3β gene transcription, which was abolished by nicotinamide. Our results demonstrated a significant and direct stimulation of Reg2 and Reg3β genes by glucocorticoids, all three were activated in response to inflammation such as in pancreatitis. Prominent stimulation of specific Reg genes by glucocorticoids may constitute a functional synergism.
Reg Proteins and Their Roles in Inflammation and Cancer of the Human Digestive System
2013, Advances in Clinical Chemistry
Citation Excerpt :
Reg1, PAP/HIP, and Reg4 are dysregulated in pancreatitis as follows. First, Reg1 expression is associated with acute pancreatitis and chronic pancreatitis, and its receptor is upregulated at the mRNA level in rat acute pancreatitis [32,93–95]. Second, Reg3/HIP/PAP is weakly or not labeled in the normal pancreas, but it is upregulated during acute pancreatitis [93,96].
The regenerating gene (Reg) family is a group of small molecules that includes four members found in various species, although only three are found in human tissues. Their expression is stimulated by certain growth factors or cytokines. The Reg family plays different roles in proliferation, migration, and anti-apoptosis through activating different signaling pathways. Their dysexpression is closely associated with a number of human conditions and diseases such as inflammation and cancer, especially in the human digestive system. Clinically, upregulation of Reg proteins is usually demonstrated in histological sections and sera from cancer patients. Therefore, Reg proteins can predict the progression and prognosis of cancers, especially those of the digestive tract, and can also act as diagnostic markers and therapeutic targets.
Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology
2012, Neurobiology of Aging
Citation Excerpt :
Although its physiological function in digestive organs remains debated (Bimmler et al., 1997; De Reggi et al., 1998), the protein tightly binds calcium carbonate crystals, suggesting an inhibitory activity on CaCO3 crystal growth, thus preventing lithiasis (Bernard et al., 1992; Geider et al., 1996; Gerbaud et al., 2000; Lee et al., 2003). It has also been shown that acute pancreatitis induces Reg1 gene expression and protein production in the pancreas (Dusetti et al., 1996; Iovanna et al., 1991). This increase of Reg1 protein is associated with Reg1 receptor messenger RNA (Kobayashi et al., 2000) suggesting that an upregulation of the receptor expression may also be important in the proliferative response of pancreatic regeneration (Bluth et al., 2006).
We analyzed the cellular distribution of the pancreatic inflammatory protein lithostathine and its receptor EXTL3 in the brain of the lemurian primate Microcebus murinus which develops amyloid deposits along with aging. In adult animals (2–4.5 years old), lithostathine and EXTL3 immunoreactivities were largely distributed in the whole brain, and more intensively in almost all cortical layers and hippocampal formation. Lithostathine was observed in the perikarya and neurites of cortical neurons but also in glial cells in the border of the ventricle and the corpus callosum. In healthy aged animals (8–13 years old), highest densities of lithostathine-containing cells were observed, mainly in occipital and parietal cortex. In aged animals with Aβ deposits, the increase in lithostathine immunoreactivity was lower as compared with aged animals. Noteworthy, lithostathine-immunopositive cells did almost never colocalize with Aβ plaques. In conclusion, lithostathine immunoreactivity in adult Microcebus murinus appeared ubiquitous and particularly in visual, sensorial, and cognitive brain areas. Immunoreactivity increased with aging and appeared markedly affected in neuropathological conditions. Its possible neuroprotection or neurodegeneration role in Alzheimer pathology deserves therefore to be investigated.
Pancreatic stone protein: A marker of organ failure and outcome in ventilator-associated pneumonia
2011, Chest
Citation Excerpt :
The study indicates that PSP/reg might mirror inflammatory and/or infectious conditions. This is not surprising since proinflammatory cytokines such as tumor necrosis factor α, interferon γ, and IL-6 are known to induce PSP/reg expression.25 Thus, PSP/reg can be assumed as a potential sepsis marker.
Ventilator-associated pneumonia (VAP) is the most common hospital-acquired, life-threatening infection. Poor outcome and health-care costs of nosocomial pneumonia remain a global burden. Currently, physicians rely on their experience to discriminate patients with good and poor outcome. However, standardized prognostic measures might guide medical decisions in the future. Pancreatic stone protein (PSP)/regenerating protein (reg) is associated with inflammation, infection, and other disease-related stimuli. The prognostic value of PSP/reg among critically ill patients is unknown. The aim of this pilot study was to evaluate PSP/reg in VAP.
One hundred one patients with clinically diagnosed VAP were assessed. PSP/reg was retrospectively analyzed using deep-frozen serum samples from VAP onset up to day 7. The main end point was death within 28 days after VAP onset.
Serum PSP/reg was associated with the sequential organ failure assessment score from VAP onset (Spearman rank correlation coefficient 0.49 P < .001) up to day 7. PSP/reg levels at VAP onset were elevated in nonsurvivors (n = 20) as compared with survivors (117.0 ng/mL [36.1-295.3] vs 36.3 ng/mL [21.0-124.0] P = .011). The areas under the receiver operating characteristic curves of PSP/reg to predict mortality/survival were 0.69 at VAP onset and 0.76 at day 7. Two PSP/reg cutoffs potentially allow for identification of individuals with a particularly good and poor outcome. Whereas PSP/reg levels below 24 ng/mL at VAP onset were associated with a good chance of survival, levels above 177 ng/mL at day 7 were present in patients with a very poor outcome.
Serum PSP/reg is a biomarker related to organ failure and outcome in patients with VAP.
ISRCTN.org; No.: ISRCTN61015974; URL: www.isrctn.org.
The identification and sequence analysis of a new Reg3gamma and Reg2 in the Syrian golden hamster
2007, Biochimica et Biophysica Acta - Gene Structure and Expression
The regenerating (Reg) genes are associated with tissue repair and have been directly implicated in pancreatic β-cell regeneration. A hamster Reg3, Islet neogenesis associated protein (INGAP), has been shown to possess anti-diabetic properties in rodent models. Although several Reg3 proteins have been identified in other species, INGAP is the only Reg3 found in hamsters. To identify new Reg3 genes in the hamster pancreas we employed homology reverse transcription polymerase chain reaction (RT-PCR) using degenerate Reg3 primers, followed by rapid amplification of cDNA ends (RACE). We report here the discovery of a new hamster Reg3 gene of 765 nucleotides (nt) that encodes a 174-amino acid (aa) protein. This protein sequence was identified as a novel hamster Reg3γ with 78% and 75% identity to the rat Reg3γ and mouse Reg3γ protein, respectively. We also fully sequenced the previously reported partial sequence of the hamster Reg1 gene coding region using RACE to yield a 756-nt transcript that encodes a deduced 173 aa protein. This protein was identified as hamster Reg2, rather than Reg1 as was initially reported, with an 81% identity to mouse Reg2. The spatial gene expression patterns of the hamster Reg genes, analyzed by RT-PCR, were similarly distributed with low level expression being found globally throughout the body. Mice and hamsters are the only species known to carry either of the functional INGAP or Reg2 genes. It remains to be determined whether these genes bestow mice and hamsters with special regenerative abilities in the pancreas.

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Regular ArticleInduction of Lithostathine/regmRNA Expression by Serum from Rats with Acute Pancreatitis and Cytokines in Pancreatic Acinar AR-42J Cells

Abstract

Regular Article
Induction of Lithostathine/regmRNA Expression by Serum from Rats with Acute Pancreatitis and Cytokines in Pancreatic Acinar AR-42J Cells