Mechanisms of action and clinical application of macrolides as immunomodulatory medications

Abstract

Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-kappaB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

FIG. 1.

Intracellular signal transduction pathways that have been proposed to be involved in macrolide immunomodulation. There are three major pathways that are influenced by macrolides. Receptor tyrosine kinases (RTKs) are receptors for many polypeptide growth factors and cytokines. RTKs such as epidermal growth factor receptor (EGFR) stimulate MEKK, and this activates the MAPK cascade. MAPK phosphorylates and activates transcription factors inducing proinflammatory genes (345). Macrolides inhibit MAPK activation, in particular, ERK1/2 activation. TLRs recognize bacterial molecules. For example, in response to LPS stimulation, TLR4 and adaptor molecules (not shown) activate the IRAK family and TAK1. TAK1 then stimulates two distinct pathways, the IKK complex and the MAPK pathway. The latter leads to the induction of AP-1, while the former activates NF-κB through the degradation of IκB proteins and the subsequent translocation of NF-κB (194). G-protein-coupled receptor (GPCR)- or RTK-mediated activation of phospholipase C (PLC) produces inositol triphosphate (IP₃). IP₃ is a ligand for the intracellular IP₃R channel of the endoplasmic reticulum's internal Ca²⁺ stores. Activation of PLC also leads to the production of diacylglycerol (DAG), which in turn activates protein kinase C (PKC). PKC and Ca²⁺/calmodulin signaling are then activated (44). Macrolides inhibit intracellular Ca²⁺ increase. Abbreviations: AP-1, activator protein 1; CaMK, calmodulin kinase; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GFR, cytokine receptor/growth factor receptor; GPCR, G-protein-coupled receptor; IKK, IκB kinase; IP₃R, inositol triphosphate receptor; IRAK, IL-1 receptor-associated kinase; MEK, MAPK/ERK kinase; PKC, protein kinase C; TAK1, transforming growth factor-activated protein kinase 1; TLR, Toll-like receptor. Blue arrows, major pathways influenced by macrolides; dashed arrows, subpathways or cross-talk pathways; red lines with “ML,” inhibition by macrolides; white bent arrow, cell response.

FIG. 2.

Beneficial effects of macrolides in the inflamed airway. In a chronically inflamed airway, there is epithelial cell damage, infiltration of inflammatory cells, goblet cell hyperplasia, hypersecretion, mucociliary dysfunction, and recurrent airway infection. Macrolides have been reported to attenuate inflammation and cellular damage in a variety of ways, as represented in this diagram. Downward-facing arrows, inhibition; upward-facing arrows, enhancement.