Human S100A9 potentiates IL-8 production in response to GM-CSF or fMLP via activation of a different set of transcription factors in neutrophils

• S100A9 does not increase cytokine production by itself in human neutrophils.
• S100A9 primes neutrophils to GM-CSF- or fMLP-induced cytokine production.
• A different set of transcription factors is involved in the priming effect of S100A9 in response to GM-CSF or fMLP.

Inflammation is highly regulated by various agents. Unexpectedly, we report here that the damage-associated molecular pattern S100A9 protein, a potent neutrophil activator and inducer of cytokine production in monocytes, is not a direct activator of cytokine production in human neutrophils. However, S100A9 primed IL-8 production in fMLP- and GM-CSF-stimulated neutrophiles via NF-κB and CREB-1, and NF-κB, STAT3 and STAT5, respectively. Pharmacological inhibition confirmed the importance of these transcription factors by significantly decreasing IL-8 production. This is the first time that a different set of transcription factors are shown to be involved in S100A9-primed neutrophils in response to proinflammatory agonist.