STAT1 phosphorylation and cleavage is regulated by the histamine (H4) receptor in human atopic and non-atopic lymphocytes.

Histamine can modulate the balance between T helper lymphocytes 1 and 2 (Th1 and Th2), and there is evidence that allergic reactions can be associated with excessive histamine production causing shifts toward Th2 responses. As signal transduction in Th-cells is specifically correlated to signal transducer and activator of transcription (STAT) activation and expression, the question arises whether histamine acting through histamine receptors (HR) induces modulation of the Janus kinase (JAK)-STAT pathway. Peripheral blood mononuclear cells (PBMC) from atopic and non-atopic donors were stimulated with phytohemagglutinin (PHA). Initial interleukin-4 (IL-4) levels were higher in the atopic group compared to the non-atopics and interferon-gamma (IFN-gamma) levels were lower. This was correlated to lower levels of STAT1 expression and phosphorylation. Furthermore, Western blots showed a 118-kDa STAT1 band at the start of the PHA stimulation that was apparently cleaved to STAT1alpha (91 kDa) and a 28 kDa-fragment with further stimulation. Histamine or the H4R agonist, clobenpropit, led to a significant suppression of the formation and phosphorylation of STAT1alpha in the non-atopic group after 48 h of PHA stimulation, but had no effect in the atopic group where STAT1alpha levels were already reduced. The STAT1alpha levels in the non-atopic group were enhanced by the H4R antagonist JNJ7777120. The phosphorylation of STAT1 could also be potentiated by the H4R antagonist, mimicking the precursor responses of STAT1alpha. JNJ7777120 also increased the binding of STAT1 to DNA and this effect could be reversed by histamine. As for histamine, the effects of the H4R antagonist were only seen in the non-atopic group. These results suggest that, in non-atopic individuals, histamine acting via the H4R can influence STAT1 regulation, but that this pathway is not present in atopics perhaps due to constitutive suppression of STAT1 activity.