PMID- 19309555 OWN - NLM STAT- MEDLINE DCOM- 20090407 LR - 20170214 IS - 0394-6320 (Print) IS - 0394-6320 (Linking) VI - 22 IP - 1 DP - 2009 Jan-Mar TI - Andolast acts at different cellular levels to inhibit immunoglobulin E synthesis. PG - 85-94 AB - The anti-asthmatic agent andolast is thought to inhibit the release of allergic mediators, but its mechanism of action is not fully understood. We investigated whether the compound inhibits immunoglobulin E (IgE) synthesis and tested the hypothesis that andolast affects immunoglobulin class switching. Interleukin (IL)-4 and the interaction of CD40 expressed on B cells with its ligand on T cells are necessary for IgE synthesis. Thus, peripheral blood mononuclear cells (PBMCs) from 40 asthmatic, 16 non-asthmatic allergic, and 9 normal donors were stimulated with IL-4 and/or anti-CD40 antibody. T cells from 9 additional allergic donors were activated with anti-CD3/CD28 antibodies to express IL-4 mRNA. After incubation in the absence or presence of test compounds, immunoglobulin concentrations were measured by enzyme immunoassay, and mRNA levels were analyzed by RT-PCR. Andolast significantly inhibited IgE synthesis by stimulated PBMCs from both asthma patients and combined allergic/normal donors. In mechanistic studies, andolast was found to act at different cellular levels. Firstly, it reduced by about 45 percent (p<0.05) the levels of IL-4 mRNA in T cells stimulated with anti-CD3/CD28. Secondly, andolast reduced by about 36 percent (p<0.05) the expression of epsilon germline transcripts in PBMCs stimulated with IL-4/anti-CD40. Thirdly, the effect of andolast on immunoglobulin synthesis was selective in that the production of IgG4 antibodies was not significantly inhibited. Our findings, while supporting the evidence that andolast is effective for the treatment of asthma, provide new insights into its mechanism of action. FAU - Malerba, M AU - Malerba M AD - Department of Internal Medicine, University of Brescia, Brescia, Italy. FAU - Mennuni, L AU - Mennuni L FAU - Piepoli, T AU - Piepoli T FAU - Caselli, G AU - Caselli G FAU - Makovec, F AU - Makovec F FAU - Rovati, L C AU - Rovati LC FAU - D' Amato, M AU - D' Amato M FAU - Ferrari, F AU - Ferrari F LA - eng PT - Journal Article PL - England TA - Int J Immunopathol Pharmacol JT - International journal of immunopathology and pharmacology JID - 8911335 RN - 0 (Anti-Asthmatic Agents) RN - 0 (Benzamides) RN - 0 (Immunoglobulin G) RN - 0 (RNA, Messenger) RN - 0 (Tetrazoles) RN - 207137-56-2 (Interleukin-4) RN - 37341-29-0 (Immunoglobulin E) RN - 6513M33209 (andolast) SB - IM MH - Anti-Asthmatic Agents/*pharmacology MH - Asthma/immunology MH - Benzamides/*pharmacology MH - Humans MH - Immunoglobulin E/*biosynthesis MH - Immunoglobulin G/biosynthesis MH - Interleukin-4/genetics MH - Leukocytes, Mononuclear/drug effects/immunology MH - RNA, Messenger/analysis MH - Tetrazoles/*pharmacology EDAT- 2009/03/25 09:00 MHDA- 2009/04/08 09:00 CRDT- 2009/03/25 09:00 PHST- 2009/03/25 09:00 [entrez] PHST- 2009/03/25 09:00 [pubmed] PHST- 2009/04/08 09:00 [medline] AID - 10 [pii] AID - 10.1177/039463200902200110 [doi] PST - ppublish SO - Int J Immunopathol Pharmacol. 2009 Jan-Mar;22(1):85-94. doi: 10.1177/039463200902200110.