Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist. E Vannier, C A Dinarello J Clin Invest. 1993;92(1):281-287. https://doi.org/10.1172/JCI116562. Research Article Histamine and IL-1 have been implicated in the pathogenesis of chronic inflammatory diseases, such as pulmonary allergic reactions and rheumatoid arthritis. We therefore investigated whether histamine modulated the synthesis of IL-1 beta. Human PBMC were stimulated with IL-1 alpha (10 ng/ml) in the absence or presence of histamine (10(-9)-10(-4) M). Histamine alone did not induce protein synthesis or mRNA accumulation for IL-1 beta. IL-1 alpha-induced IL-1 beta synthesis was enhanced two to threefold by histamine concentrations from 10(-6)-10(-4) M. Cimetidine, an H2 receptor antagonist, reversed the histamine (10(-5) M)-mediated increase in IL-1 alpha-induced IL-1 beta synthesis. Diphenhydramine, an H1 receptor antagonist, had no effect. Indomethacin, a cyclooxygenase inhibitor, significantly reduced IL-1 alpha-induced IL-1 beta synthesis, but had no effect on the histamine-mediated increase in IL-1 alpha- induced IL-1 beta synthesis. Histamine (10(-5) M) enhanced and sustained IL-1 beta mRNA levels in IL-1 alpha- stimulated PBMC. However, histamine reduced IL-1 beta mRNA half-life (2.4 vs 1.2 h), suggesting that histamine enhances IL-1 alpha-induced IL-1 beta synthesis at the level of transcriptional activation. On the other hand, histamine (10(-5) M) did not affect IL-1 alpha-induced synthesis of IL-1 receptor antagonist. These results suggest that mast cells may sustain chronic inflammatory processes by upregulating self-induction of IL-1 through histamine release. Find the latest version: https://jci.me/116562/pdf Histamine Enhances Interleukin (IL)-1-induced IL-1 Gene Expression and Protein Synthesis via H2 Receptors in Peripheral Blood Mononuclear Cells Comparison with IL-1 Receptor Antagonist Edouard Vannier and Charles A. Dinarello Department ofMedicine, Tufts University School ofMedicine, and New England Medical Center, Boston, Massachusetts 02111 Abstract linkage, mast cells also synthesize a wide array of cytokines, including IL- 1, TNF-a, IL-3, IL-5, and GM-CSF ( 1-4) which, Histamine and IL-1 have been implicated in the pathogenesis in turn, activate eosinophil functions. Stimulation of the low of chronic inflammatory diseases, such as pulmonary allergic affinity receptors for IgE (FcERII) on monocytes also result in reactions and rheumatoid arthritis. We therefore investigated the production of IL-1A and TNF-a (5). Therefore, cytokine whether histamine modulated the synthesis of IL-1,8. Human synthesis by mast cells and monocytes may contribute to the PBMC were stimulated with IL-la (10 ng/ml) in the absence onset of the late phase response. or presence of histamine (10-'-10-4 M). Histamine alone did IL-1 may play an important role in eosinophil accumula- not induce protein synthesis or mRNA accumulation for IL-1(3. tion during the late phase response. Recent evidence supports IL-la-induced IL-1,8 synthesis was enhanced two to threefold this concept since blockade of IL- 1 by the naturally occurring by histamine concentrations from 106`404 M. Cimetidine, an IL- 1 receptor antagonist (IL-l Ra) reduces eosinophil infiltra- H2 receptor antagonist, reversed the histamine (10' M)- tion in lungs after inhalation of antigen by sensitized guinea mediated increase in IL-ia-induced IL-1i( synthesis. Diphen- pigs (6). Related to these events, IL-1 upregulates the expres- hydramine, an H1 receptor antagonist, had no effect. Indo- sion of vascular cell adhesion molecule- 1 and intercellular ad- methacin, a cyclooxygenase inhibitor, significantly reduced hesion molecule- 1 on endothelial cells (7, 8). Eosinophils con- IL-la-induced IL-il3 synthesis, but had no effect on the hista- stitutively express the integrin very late antigen-4 ( 9 ) that recog- mine-mediated increase in IL-la-induced IL-10B synthesis. nizes vascular cell adhesion molecule- 1 (10). Blockade of Histamine (10'- M) enhanced and sustained IL-1,8 mRNA intracellular adhesion molecule- 1 prevents both the eosinophil levels in IL-la-stimulated PBMC. However, histamine re- accumulation in the primate lung and the subsequent bron- duced IL-lfl mRNA half-life (2.4 vs 1.2 h), suggesting that chial hyperreactivity to acetylcholine ( 11). Moreover, high af- histamine enhances IL-la-induced IL-103 synthesis at the level finity receptors for human IL-3, IL-5 or GM-CSF are com- of transcriptional activation. On the other hand, histamine prised of an a chain, specific for each cytokine, and of a com- (10-' M) did not affect IL-la-induced synthesis of IL-1 recep- mon ,B chain ( 12, 13). A role for IL- 1 also exists in this response tor antagonist. These results suggest that mast cells may sus- since IL- 1 upregulates the expression of the ( chain ( 14). tain chronic inflammatory processes by upregulating self-in- Since acute allergic asthma is characterized by both mast duction of IL-1 through histamine release. (J. Clin. Invest. cell degranulation and IL- 1 production, we investigated the 1993.92:281-287.) Key words: allergy * mast cells * prostaglan- effect ofhistamine on the synthesis ofIL- 13 and IL- I Ra. Modu- dins * cytokines - mRNA stability lation by histamine ofgene expression and total cellular synthe- sis of IL- 1,B and IL- 1 Ra were studied in human PBMC stimu- Introduction lated with either LPS or IL- 1 itself. Although mast cell activation is the initial event in acute aller- Methods gic asthma, the event is often followed by a sustained inflamma- tory reaction that is characterized by a predominantly eosino- Human PBMC culture. Blood was drawn from healthy human volun- philic infiltration. Cross-linkage of the high affinity receptors teers who had not taken any histamine receptor antagonists or cycloox- for IgE (FcERI)' on mast cells induces release ofpreformed and ygenase inhibitors for -2 wk. The study was approved by the Human newly synthesized mediators, such as histamine and arachi- Investigative Review Committee of The New England Medical Center donic acid metabolites. However, in response to FcERI cross- Hospitals. PBMC were separated from heparinized blood by centrifuga- tion on Ficoll-Hypaque (Ficoll Type 400; Sigma Chemical Co., St. Louis, MO, and Hypaque-M 90%; Winthrop Breon Laboratories, New Address correspondence and reprint requests to Charles A. Dinarello, York) gradients. Cells were washed twice in 0.15 M NaCl and resus- New England Medical Center, 750 Washington Street, Boston, MA pended at 5 x 106 cells/ml in ultrafiltered RPMI culture medium 1640 02111. (Whittaker Bioproducts, Walkersville, MD) supplemented with 2 mM Receivedfor publication 5 June 1992 and in revisedform 19 Jan- L-glutamine, 100 U/ml penicillin, and 100 ,ug/ml streptomycin uary 1993. (Gibco Laboratories, Grand Island, NY). PBMC (2.5 X 106 cells/ml in RPMI containing 1% heat-inactivated human AB serum) were stimu- 1. Abbreviations used in this paper: FcERI, high affinity receptors for lated with LPS from Escherichia coli 055:B5 ( 10 ng/ml; Sigma Chemi- IgE; FcERII, low affinity receptors for IgE; IL- I Ra, IL- I receptor antago- cal Co.) or human recombinant IL-la (10 ng/ml; kindly provided by nist. Dr. P. Lomedico, Hoffmann-LaRoche Inc., Nutley, NJ) in the absence or presence of either histamine ( I0 -9-10-4 M, Sigma Chemical Co.) or J. Clin. Invest. PGE2 (0.1-1,000 ng/ml, Sigma Chemical Co.). PBMC cultures were © The American Society for Clinical Investigation, Inc. incubated in 12 x 75-mm polypropylene round bottom tubes (Becton 0021-9738/93/07/281/07 $2.00 Dickinson Co., Lincoln Park, NJ) for 24 h at 37°C in a humidified Volume 92, July 1993, 281-287 atmosphere containing 5% CO2. Histamine Enhances IL-l-induced IL-I Synthesis via H2 Receptors 281 In other experiments, PBMC (5 x 106 cells/ml) were pre-incu- Figure 1. Effect of his- bated for 1 hat 370C in the presence of either 1.3 x 10-6 M indometha- tamine on IL- a- cin (Sigma Chemical Co.), 10-' M diphenhydramine (Elkins-Sinn, induced synthesis of Inc., Cherry Hill, NJ), from 10-6 to I0-4 M cimetidine (Smith Kline & IL-I. PBMC were French, Philadelphia, PA), l0' M ranitidine (Glaxo Inc., Research 4 stimulated for 24 h with Triangle Park, NC), 1 Ag/ml IL-lRa (kindly provided by Dr. R. C. IL-la (10 ng/ml) in Thompson, Synergen, Inc., Boulder, CO), or RPMI as a control. 3 the absence (-) or pres- Cytokine RIAs. After incubation, cultures were subjected to three ence of histamine (HIS: freeze-thaw cycles. This procedure is optimal for recovery and measure- 10-9-10-4 M). Differ- ment of total (cell-associated and secreted) cytokines by specific RIAs 2- ences in IL-I, synthesis as described for IL- I(3 ( 15) and IL- I Ra ( 16). The sensitivities (defined were analyzed for sig- as 95% binding) of RIAs for IL-lI and IL-lRa were 63±12 (n = 13) nificance by ANOVA and 78±11 (n = 4) pg/ml, respectively. In (**P < 0.01; ***P RNA isolation and Northern analysis. PBMC were stimulated for 4, < 0.001). Data are ex- 8, 16, or 32 h at 370C in 50 ml polypropylene tubes with IL-la (10 HIS - -9 -8 -7 -6 -5 -4 pressed as mean±SEM ng/ml) in the absence or presence of histamine ( l0-7-l0-4 M). Total IL-la + + + + + + + for four donors. cellular RNA was then extracted from PBMC by lysis with 4 M guani- dium isothiocyanate followed by ultracentrifugation on a 5.7-M ce- sium chloride gradient ( 17).