Role of Histamine in Modulating the Immune Response and Inflammation

Abstract

Inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, and leukotrienes, impact the immune system, usually as proinflammatory factors. Other mediators act as regulatory components to establish homeostasis after injury or prevent the inflammatory process. Histamine, a biogenic vasoactive amine, causes symptoms such as allergies and has a pleiotropic effect that is dependent on its interaction with its four histamine receptors. In this review, we discuss the dualistic effects of histamine: how histamine affects inflammation of the immune system through the activation of intracellular pathways that induce the production of inflammatory mediators and cytokines in different immune cells and how histamine exerts regulatory functions in innate and adaptive immune responses. We also evaluate the interactions between these effects.

Figure 1

Intracellular activation cascades triggered by histamine receptors (HRs). The pleiotropic effects of histamine are mediated by four histamine receptors: H1R, H2R, H3R, and H4R, which are G protein-coupled receptors. Signaling via H1R leads to activation of intracellular transcription factors, such as PLC (phospholipase C), IP3 (inositol triphosphate), PKC (protein kinase C), DAG (diacylglycerol), and Ca²⁺. H2R signaling acts through activation of adenylyl cyclase (AC), which increases cyclic adenosine monophosphate (cAMP) levels and activates protein kinase A (PKA), while H3R and H4R inhibit this cascade. Those intracellular signaling pathways culminate into protein phosphorylation and transcription of nuclear factor such as nuclear factor kappa B (NF-κB), nuclear factor of activated T-cells (NFAT), cAMP response element binding protein (CREB), and activator protein 1 (AP-1).

Figure 2

Inflammatory and regulatory functions of histamine on different body sites. Histamine plays dual functions according to the cell type and the receptor. As an inducer of inflammation, histamine can contribute to pulmonary fibrosis, cardiovascular diseases and atherosclerosis, atopic dermatitis, central nervous system damage, and colitis in some experimental models, besides favoring the polarization of the immune response to a Th1 profile. On the other hand, histamine can regulate inflammation in models of experimental autoimmune encephalomyelitis (EAE) and colitis, favor wound healing in skin lesions, and inhibit tumour development. Also, microbiota-derived histamine can regulate the inflammatory picture of asthma. Red arrows indicate proinflammatory action; green arrows indicate regulatory action of histamine.