H. pylori–induced proinflammatory responses are dependent on the presence in H. pylori of a functional type IV secretion system (T4SS), which delivers effector molecules, such as cell wall peptidoglycan (PGN) and the protein CagA, to epithelial cells. The precise mechanisms by which the H. pylori T4SS mediates effector delivery to host cells are, however, presently unknown. (i) Recognition of H. pylori PGN by the cytosolic host defense molecule NOD1 leads to NF-κB activation. On the basis of studies with Shigella flexneri, it is likely that NOD1 activates NF-κB via caspase-recruitment domain (CARD)–CARD interactions with receptor-interacting serine-threonine kinase (RICK; also known as RIP2). Activated NF-κB complexes translocate to the nucleus, where they upregulate expression of genes encoding the proinflammatory chemokines IL-8 and CXC-chemokine ligand 2 (CXCL2; also known as MIP2) and the antimicrobial peptide human β-defensin-2 (hBD-2). (ii) CagA translocation into epithelial cells by certain H. pylori strains able to induce high levels of IL-8 is also accompanied by the induction of an inflammatory response. Tyrosine phosphorylation of EPIYA motifs on CagA triggers a signaling cascade that involves the Ras-dependent kinases ERK1 and ERK2, leading to activation of the transcription factors NF-κB and activator protein-1 (AP-1) and, ultimately, IL-8 production by host cells. Courtesy of R. Ferrero (Monash University, Clayton, Victoria, Australia).