H1 antihistamines in allergic rhinitis: The molecular pathways of interleukin and toll - like receptor systems

The complex interaction between inflammatory mediators in allergic rhinitis (AR) is determined by the role of genetic polymorphisms, including interleukin (IL) and toll-like receptor (TLR) genes. This study aimed to discuss the effects of H1-antihistamines on IL and TLR systems. Several ILs involved in AR pathogenesis are: IL-4 (rs2243250, rs1800925, rs1801275, rs2227284, rs2070874), IL-6 (rs1800795, rs1800797), IL-10 (rs1800871, rs1800872), IL-12R (rs438421), IL-13 (rs1800925, rs20541), IL-17 (rs3819024), IL-18 (rs360721, rs360718, rs360717, rs187238), IL-23R (rs7517847), and IL-27 (rs153109, rs17855750). In the IL system, histamines stimulate the IL production in Type 2 helper T (Th2) cells through protein kinase A (PKA), janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, and the activation of H1-histamine receptor and histidine decarboxylase (HDC) genes. On contrary, antihistamines down-regulate the H1-histamine receptor gene expression through the transcription suppression of HDC and IL genes and suppress histamine basal signaling through the inverse agonistic activity. TLRs involved in AR pathogenesis are TLR2 (rs4696480, rs3804099, rs5743708), TLR4 (rs4986790), TLR6 (rs2381289), TLR7 (rs179008, rs5935438), TRL8 (rs2407992, rs5741883, rs17256081, rs4830805, rs3788935, rs178998), and TLR10 (rs11466651). In the TLR system, histamines trigger the TLR expression by stimulating interferon-γ (IFN-γ) to up-regulate mast cells and by stimulating receptor-interacting protein (RIP) to activate IκB kinase-β. Contrastingly, antihistamines suppress TIR-domain-containing adaptor protein inducing IFN-β (TRIF) and RIP protein and thus inhibit the expression of TLR. In addition, several studies indicated that H1-antihistamines inhibit the IL and TLR systems indirectly.