ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 330, No. 1, June 1, pp. 129–132, 1996 Article No. 0234 Induction of Lithostathine/ reg mRNA Expression by Serum from Rats with Acute Pancreatitis and Cytokines in Pancreatic Acinar AR-42J Cells Nelson J. Dusetti, Gustavo V. Mallo, Emilia M. Ortiz, Volker Keim, Jean-Charles Dagorn, and Juan L. Iovanna 1 U.315 INSERM, 46 Boulevard de la Gaye, F-13009 Marseille, France Received December 22, 1995, and in revised form February 19, 1996 mRNA concentrations increased dramatically (2 – 4). A During the acute phase of pancreatitis, expression moderate increase was also observed for lithostathine/ of most pancreatic enzymes decreases, whereas reg (5), the only described pancreatic protein with sig- mRNAs of pancreatitis associated protein and litho- nificant structural similarity to the PAPs. Contrary to stathine/reg increase dramatically. In the present the PAPs, lithostathine/reg is expressed at moderate study we have investigated the effect of serum from levels in normal pancreas. In addition, PAPs and lith- rats with acute pancreatitis (SAP) and cytokines on ostathine/reg displayed marked homology with the car- the lithostathine/reg mRNA expression in AR-42J cells. boxy-terminal region of C-type animal lectins (6), Lithostathine/reg mRNA was strongly induced by SAP which probably explains their capacity for aggregating in a dose-dependent manner. Induction was abolished bacteria (2, 7). The spectacular overexpression of PAPs by preheating the SAP or by treating the cells with and lithostathine/reg during pancreatitis and their cycloheximide. Treatment with interleukins (IL) IL-1 properties of controlling bacterial proliferation suggest or IL-6 or dexamethasone alone was ineffective. Com- that these proteins are an important component of the bination of IL-1 with IL-6 was also ineffective. Combi- mechanism of defense against pancreatic aggression. nation of IL-6 with dexamethasone resulted in strong Structures of genes encoding PAP I, II, and III and induction of the lithostathine/reg gene, but the further lithostathine/reg have been determined (3, 4, 8, 9). All addition of IL-1 to the mixture reduced induction. four genes are organized in six exons, and similarities Treatment with tumor necrosis factor-a (TNFa) or in- observed in their coding sequences extend to their pro- terferon-g (IFNg) induced lithostathine/reg mRNA moter regions, suggesting possible common mecha- expression. Combination of dexamethasone with nisms of activation. In addition, the four genes have TNFa or IFNg showed an inhibitory effect on litho- been located to the same position on chromosome stathine/reg mRNA expression. These findings suggest 4q33 – 34 (10), suggesting that they derived from the that expression of the lithostathine/reg mRNA during same ancestral gene by gene duplication. acute pancreatitis could be mediated by specific com- binations of cytokines and/or glucocorticoids.  1996 In previous works, we have demonstrated the pres- Academic Press, Inc. ence of a factor in serum from rats with acute pancre- atitis, but not from healthy rats, capable of inducing PAP I gene expression in the pancreatic acinar cell line AR-42J (11). As a first step to determine the molecular A rapid and massive rearrangement of the pattern of pancreatic gene expression was observed during the mechanism of the lithostathine/reg gene induction dur- ing acute pancreatitis, we have investigated the effect acute phase of pancreatitis (1). Whereas the concentra- tion of most messenger RNAs encoding pancreatic en- of serum from rats with acute pancreatitis on lithos- tathine/reg mRNA expression in AR-42J cells. In addi- zymes decreased significantly, PAP I, 2 II, and III tion, because the rapid and strong induction of PAP I, II, and III and lithostathine/reg during acute pancreati- 1 To whom correspondence should be addressed. Fax: (33) 91 26 62 19. 2 Abbreviations used: PAP, pancreatitis associated protein; TNFa, tumor necrosis factor-a; IFNg, interferon-g; IL, interleukin; SAP, trate; SH, serum from healthy rats; SSO, serum from sham-operated rats; SSPE, standard saline phosphate EDTA. serum from rats with acute pancreatitis; SSC, standard saline ci- 129 0003-9861/96 $18.00 Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved.