TISSUE-SPECIFIC PROTEIN KINASE C ISOFORMS DIFFERENTIALLY MEDIATE MACROPHAGE TNFα AND IL-1β PRODUCTION

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Abstract
Macrophage subpopulations are differentially activated during sepsis, shock, or trauma; however, it is unknown whether inherent mechanistic and phenotypic differences exist between macrophage subpopulations that may account for region-specific inflammation. We hypothesized that macrophage expression/function of protein kinase C (PKC) isoforms is tissue specific (alveolar versus peritoneal). Rat alveolar and peritoneal macrophages were each probed for the expression of PKC isoforms α, β1, β2, γ, δ, ∈, ζ, and θ by immunoblot. PKC isoforms α, β1, β2, γ, and η were detected in both populations; however, isoforms ∈, γ, and η were found in alveolar macrophages only. To investigate the functional role of the Ca2+-dependent PKC (cPKC) versus Ca2+-independent PKC (nPKC) isoforms, pan-PKC isoform inhibition (cPKC and nPKC), or cPKC isoform selective inhibition (β, β1, β2, γ) was performed before endotoxin (lipopolysaccharide, Salmonella minnesota, 100 ng/mL) stimulation in vitro. Pan-PKC isoform inhibition attenuated TNFα and IL-1β production by each population; however, selective cPKC (α, β1, β2, γ) inhibition decreased peritoneal, but not alveolar, macrophage TNFα production. IL-1β production was not affected by cPKC inhibition in either population. Conclusions: 1) alveolar and peritoneal macrophages constitutively express different PKC isoforms; 2) alveolar macrophages uniquely express isoforms ∈, γ, η 3) TNFα production is regulated by cPKCs in peritoneal macrophages, but by nPKCs in alveolar macrophages; 4) nPKCs regulate IL-1β production in both populations. These results suggest that tissue-specific PKC isoforms differentially mediate macrophage function, which may have important regulatory implications in the compartmentalization of immune function. Further understanding may allow region-specific manipulation of inflammation.

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