Doxycycline and IL-8 Modulation in a Line of Human Alveolar Epithelium: More Evidence for the Anti-Inflammatory Function of Some Antimicrobials
Beta blockers for severe systolic dysfunction; antibiotics for peptic ulcer disease. These are just a few examples of the many unpredicted consequences of medication intervention. Rheumatology has known of the disease modifying anti-rheumatic drug (DMARD) capacity of second generation tetracyclines including doxycycline (1). This has actually led to investigations attempting to identify organisms possibly serving as substrates for inflammatory processes including rheumatoid arthritis and even atherosclerosis. Generally, this has been unsuccessful and the conclusion that doxycycline has intrinsic anti-inflammatory properties has become suspect (2,3).
Experience with higher generation macrolides like azithromycin further lends credence to this concept of antibiotics as intrinsically anti-inflammatory (4). There is a body of data suggesting inhibition of cytokine expression by this drug. In diseases like cystic fibrosis where even very high intracellular concentrations of macrolide have no significant activity against pseudomonas species but the drug therapy does appear to modify disease course further supports this anti-inflammatory contention (5).
Published work has suggested the beneficial anti-inflammatory effect in COPD relating this broadly to doxycycline’s inhibition of matrix metalloproteinases, MMP(s) (6). MMP(s) have been postulated to rise as a function of the oxidative stress recurrently demonstrated in chronic obstructive pulmonary disease (COPD). Additionally, doxycycline has demonstrated the ability to impair neutrophil migration in LPS stimulated alveolar macrophages harvested from bronchoalveolar lavage. Hoyt et al. (7) have now nicely demonstrated ex-vivo that doxycycline is capable of inhibiting IL-8 expression in a line of human lung epithelial cells stimulated by a cytomix, a potent combination of inflammatory stimulators. Importantly, this is a demonstration of measureable inhibition of an inflammatory cytokine by the tetracycline in mammalian cells.
The biologic significance of this still remains to be fully determined. In the large ECLIPSE TRIAL, the major discriminator of inflammatory modulators in COPD with inflammation was IL-6 and not IL-8 which actually decreased in the cohort of individuals with evidence of inflammation (8). Further study may reveal that doxycycline also has a suppressive effect on the former cytokine.
Broadly, MAP kinases are a group of protein kinases that participate in the signaling of stress related mediators like cytokines. A finding reported by Hoyt et al. (7) that will require further investigation concerns the decrease in p38 mitogen-activated protein kinase (p38 MAPK) in response to doxycycline. The data in this regard remains conflicting with reports suggesting p38 MAPK is involved in IL-8 transcription in a human monocyte model with exposure to Clostridium difficile toxin (9). Hoyt et al. (7) found a decrease in p38 MAPK along the absence of change in mRNA by reverse transcription-polymerase chain reaction (RT-PCR) suggesting that effect of doxycycline on IL-8 elaboration is post transcriptional. Others have reported data supporting the concept of post transcription modulation of IL-8 by doxycycline as suggested by Hoyt et al. (10). While validation with repeat studies will be necessary, the finding that IL-8 mRNA by RT-PCR was not affected by levels of doxycycline that inhibited IL-8 is noteworthy. One may conclude that IL-8 assembly at the level of the ribosome could be operative. While it was previously presumed that the tetracyclines specifically targeted bacterial ribosomes, Robbins et al along with all the other studies support the anti-inflammatory effect of tetracyclines in human disease and demonstrates that mammalian cells are also affected by this moiety.
So Hoyt et al. (7) have added to the knowledge base by definitively demonstrating the non-antimicrobial properties of doxycycline by ex-vivo inhibition of IL-8 production in a line stimulated mammalian alveolar epithelial cells. If the RT-PCR data can be further confirmed, this inhibition of IL-8 by doxycycline appears to be a post-transcriptional mechanism. Whether p38 MAPK is a transcriptional or post-transcriptional cytokine modifier remains to be determined.
Jay E. Blum, M.D.
Chief, Pulmonary and Critical Care
Phoenix VA Medical Center
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- Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation.1999;99:1540-7.
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- Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23:590-615.
- Equi AC, Davies JC, Painter H, Hyde S, Bush A, Geddes DM, Alton E. Exploring the mechanisms of macrolides in cystic fibrosis. Respir Med. 2006;100:687-97.
- Greenwald RA, Moak SA, Ramamurthy NS, Golub LM. Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J Rheumatol. 1992;19:927-38.
- Hoyt JC, Ballering JG, Hayden JM, Robbins RA. Doxycycline decreases production of interleukin-8 in a549 human lung epithelial cells. Southwest J Pulm Crit Care. 2013;6:130-42.
- Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, Lomas DA, Duvoix A, MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agustí A; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065-72.
- Warny M, Keates AC, Keates S, Castagliuolo I, Zacks J, Aboudola S et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest. 2000;105:1147–56.
- Li J, Kartha S, Iasvovskaia S, Tan A, Bhat RK, Manaligod JM, Page K, Brasier AR and Hershenson MB. Regulation of human airway epithelial cell IL-8 expression by MAP kinases. Am J Physiol Lung Cell Mol Physiol. 2002;283:L690-L699.
Reference as: Blum JE. Doxycycline and IL-8 modulation in a line of human alveolar epithelium: more evidence for the anti-inflammatory function of some antimicrobials. Southwest J Pulm Crit Care. 2013;6(4):184-6. PDF