Erythromycin inhibits beta2-integrins (CD11b/CD18) expression, interleukin-8 release and intracellular oxidative metabolism in neutrophils.
Macrolides have therapeutic benefits on chronic inflammatory airway diseases. Thus, macrolides are supposed to have variable biological effects apart from antimicrobial activity. Neutrophil adherence and influx with oxidants and cytokines production implicates involvement in airway inflammation. To investigate whether erythromycin (EM) affects neutrophil activity in vitro, lipopolysaccharide (LPS)-treated neutrophils were continuously incubated for 4 h in the absence or presence of increasing doses of EM from 1 microg ml(-1) to 100 microg ml(-1) in the last 2 h. Leukocyte adhesion molecules Mac-1 and intracellular H2O2(DCFH) were determined by flowcytometric assay. IL-8 and TNFalpha in supernatant was measured by ELISA method. The expression of Mac-1 and mean intracellular DCF fluorescence intensity (DCFH) of neutrophils significantly increased after stimulation with LPS. Pretreatment with EM significantly decreased LPS induced Mac-1 expression on neutrophils compared with LPS stimulation only. EM alone (100 microg ml(-1)) also decreased Mac-1 expression on neutrophils. EM significantly reduced the LPS-increased DCFH. EM alone (100 microg ml(-1)) also caused a decrease in DCFH. Increasing doses of EM also significantly decreased the IL-8 released by LPS-stimulated neutrophils. In conclusion, EM exerts a direct effect on the neutrophils by downregulating the expression of beta2-integrin on neutrophils, thus leading to a decrease in the intracellular H2O2, as well as the production of IL-8. Our conclusion provides an explanation for the clinical efficacy of erythromycin in neutrophil-mediated airway inflammation.
Lin
H C
HC
Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan.
Wang
C H
CH
Liu
C Y
CY
Yu
C T
CT
Kuo
H P
HP
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018821:CD18 Antigens / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004917:Erythromycin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D004917:Erythromycin; D006861:Hydrogen Peroxide