Schematic representation of the mechanisms by which interleukin-8 (IL-8)/cytokine-induced neutrophil chemokine (CINC)-1 and transforming growth factor (TGF)-β1 have a synergistic inhibitory effect on the β₂-adrenergic receptor (β₂AR) signaling pathway in type II alveolar (ATII) cells. IL-8/CINC-1 and TGF-β1 cause the activation of different phosphoinositide 3-kinase (PI3K) isoforms. However, IL-8/CINC-1 but not TGF-β1 phosphorylates G-protein–coupled receptor kinase 2 (GRK2) via a protein kinase C-zeta (PKC-ζ)–dependent mechanism explaining why the blockade of IL-8/CINC-1 prevents the TGF-β1–mediated inhibition of the β₂AR signaling pathway in ATII cells. This results in the translocation of the protein complex GRK2 and PI3K to the cell membrane. This protein complex causes phosphorylation at the Ser355 heterologous desensitization and downregulation of the β₂AR in ATII cells. IL-8/CINC-1 and TGF-β1 then prevent the activation of 3′-5′-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway that upregulates the vectorial fluid transport across the alveolar epithelium via phosphorylation and increased expression of cystic fibrosis transmembrane conductance regulator (CFTR) at the plasma membrane of ATII cells. The solid lines indicate the pathways stimulated by IL-8/CINC-1 and the dashed lines indicate the pathways inhibited by these mediators.