Spleen Tyrosine Kinase (Syk)-dependent Calcium Signals Mediate Efficient CpG-induced Exocytosis of Tumor Necrosis Factor α (TNF α) in Innate Immune Cells

Pattern recognition receptors expressed by cells of the innate immune system initiate the immune response upon recognition of microbial products. Activation of pattern recognition receptors result in the production and release of proinflammatory cytokines, including TNF alpha and IL-6. Because these cytokines promote disparate effector cell responses, understanding the signaling pathways involved in their regulation is critical for directing the immune response. Using macrophages and dendritic cells deficient in spleen tyrosine kinase (Syk), we identified a novel pathway by which TNF alpha trafficking and secretion are regulated by Syk following stimulation with CpG DNA. In the absence of PLC gamma 2, a Syk substrate, or the calcium-responsive kinase calcium calmodulin kinase II, CpG-induced TNF alpha secretion was impaired. Forced calcium mobilization rescued the TNF alpha secretion defect in Syk-deficient cells. In contrast to its effect on TNF alpha, Syk deficiency did not affect IL-6 secretion, suggesting that Syk-dependent signals participate in differential sorting of cytokines, thus tailoring the cytokine response. Our data report a novel pathway for TNF alpha regulation and provide insight into non-transcriptional mechanisms for shaping cytokine responses.