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.