LPS-stimulated cytokine production in type I cells is modulated by the renin-angiotensin system.
The alveolar epithelium serves as a barrier to the entry of potential respiratory pathogens. Alveolar Type II (TII) cells have immunomodulatory functions, but whether Type I (TI) cells, which comprise approximately 95% of the alveolar epithelium, also play a role in immunity is unknown. Because the renin-angiotensin system (RAS) is emerging as an important mediator of inflammation, and angiotensin-converting enzyme 2 (ACE2), an element of the RAS, has been implicated in lung injury, we hypothesize that TI cells can produce cytokines in response to LPS stimulation, and that this inflammation can be modulated by the RAS. Alveolar TI cells were isolated from adult Sprague-Dawley rat lungs that had been injured with an intratracheal instillation of LPS. PCR was performed to determine whether TI cells expressed transcripts for TNF-α, IL-6, or IL-1β at baseline and after lung injury. Immunocytochemical and protein analysis detected angiotensin II (Ang II) and ACE2, as well as angiotensin Type 1 receptor (AT1R) and Type 2 receptor (AT2R), in TI cells. To separate cell-specific responses, primary TI cells were isolated, cultured, and exposed to LPS, Ang II, or specific inhibitors of AT1R or AT2R. Cytokine production was assayed by ELISA. LPS stimulated the production of all cytokines, whereas ACE2 and losartan, an AT1R inhibitor, blocked elements of the LPS-induced cytokine response. Primary TI cells produce cytokines when treated with LPS, contain important components of the RAS, and can modulate LPS-induced cytokine production via the RAS, suggesting a role for TI cells in the innate immune response of the lung.
San Francisco VA Medical Center, 4150 Clement St., San Francisco, CA 94121, USA.
Mandi H
MH
Wong
Olivia C
OC
Chapin
Meshell D
MD
Johnson
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4