Topical Azithromycin and Clarithromycin Inhibit Acute and Chronic Skin Inflammation in Sensitized Mice, with Apparent Selectivity for Th2-Mediated Processes in Delayed-Type Hypersensitivity

Abstract

Macrolide antibiotics inhibit the secretion of Th1 cytokines while their effects on the release of Th2 cytokines are variable. We investigated molecular and cellular markers of Th1- and Th2-mediated inflammatory mechanisms and the anti-inflammatory activity of azithromycin and clarithromycin in phorbol 12-myristate 13-acetate (PMA) and oxazolone (OXA)-induced skin inflammation. Dexamethasone (50 μg/ear), azithromycin, and clarithromycin (500 μg/ear) reduced TNF-α and interleukin (IL)-1β concentration in ear tissue by inhibiting inflammatory cell accumulation in PMA-induced inflammation. In OXA-induced early delayed-type hypersensitivity (DTH), the macrolides (2 mg/ear) and dexamethasone (25 μg/ear) reduced ear tissue inflammatory cell infiltration and secretion of IL-4 while clarithromycin also decreased IFN-γ concentration. Macrolides showed better activity when administered after the challenge. In OXA-induced chronic DTH, azithromycin (1 mg/ear) reduced the number of ear tissue mast cells and decreased the concentration of IL-4 in ear tissue and of immunoglobulin (Ig)E in serum. Clarithromycin (1 mg/ear) reduced serum IgE concentration, possibly by a mechanism independent of IL-4, while both macrolides attenuated mast cell degranulation. In conclusion, azithromycin and clarithromycin attenuate pro-inflammatory cytokine production and leukocyte infiltration during innate immune reactions, while selectively affecting Th2 rather than Th1 immunity in DTH reactions.

Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury

“…These key findings are consistent with observations of AZM-mediated changes in macrophage phenotype in models of lung infection, skin inflammation, and sepsis [ 17 , 19 , 31 ]; however, the results reported here are the first to document that AZM can have a similar effect after traumatic CNS injury. While pro-inflammatory macrophage activation is reduced with AZM treatment in acute conjunctiva [ 32 ], to the best of our knowledge, the current results are the first to demonstrate that AZM, or any other macrolide antibiotic, alters macrophage phenotype in response to spinal cord injury and reduces macrophage neurotoxicity.…”

“…One observation in this study was that AZM treatment decreased monocyte-derived macrophages in the injured spinal cord. This is consistent with observations of reduced inflammation and macrophage accumulation with AZM treatment in models of acute conjunctiva, lung infection, and skin inflammation [ 17 , 19 , 32 ]. In addition, decreasing macrophage accumulation at the site of SCI is neuroprotective and facilitates recovery [ 42 ].…”

The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms

“…Although the effect of macrolides on eosinophils has been less commonly investigated, a few studies report decreased eosinophil counts, and concentration of ECP (a ribonuclease secreted by eosinophils responsible for local cytotoxic effect). This suggests that there may be a role for the use of macrolides in allergic chronic inflammatory diseases ( 43 , 74 , 75 ). The possible influence of macrolides on eosinophilic inflammation is further supported by the finding that Th2 cytokines, such as IL-4 and IL-5, are more frequently reduced than Th1 cytokines, such as IL-2 and INF-gamma ( 19 , 20 , 22 , 32 , 42 , 43 , 53 , 55 , 56 ).…”

Macrolides for the treatment of chronic bacterial prostatitis: An effective application of their unique pharmacokinetic and pharmacodynamic profile (Review)

“…In this respect, it is worth mentioning that, at least in mice, prolonged macrolide treatment is able to selectively modulate T cell-mediated immune responses in vivo (58). Clearly, there is much to be gained clinically from investigation of the effects of macrolides on host defence responses in CP.…”