Signaling pathway studies were performed to determine the effect of histamine on cAMP production and the role of PKA activity in TNF suppression. A. Treatment of activated THP-1 cells with L. reuteri 6475 CM or histamine increased intracellular cAMP. The increase in cAMP was blocked by a specific H2 receptor antagonist, ranitidine. Results represent the mean ± SD (n = 2), *p value<0.05 compared to medium control, **p value<0.05 compared to L. reuteri 6475, #p value<0.05 compared to histamine. B. Inhibition of PKA activity partially blocked TNF suppression by TNF-inhibitory compounds L. reuteri 6475 CM, HILIC-HPLC fraction B3, histamine, and dcAMP. Results represent the mean ± SD (n = 9), *p value<0.05 compared to H89 treated samples.