Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation.
Severe combined immunodeficient (SCID) mice lack functional lymphocytes and therefore develop Pneumocystis carinii pneumonia. However, when infected SCID mice are immunologically reconstituted with congenic spleen cells, a protective inflammatory cascade is initiated. Proinflammatory cytokines are produced, and lymphocytes and macrophages are recruited specifically to alveolar sites of infection. Importantly, uninfected regions of the lung remain free from inflammatory involvement, suggesting that there are specific mechanisms that limit inflammation in the infected lung. Therefore, to determine whether chemokines are involved in targeting the P. carinii-driven inflammatory response, steady-state mRNA levels of several chemokines were measured in the lungs of both reconstituted and nonreconstituted P. carinii-infected SCID mice. Despite significant organism burdens in the lungs of 8- and 10-week-old SCID mice, there was no evidence of elevated chemokine gene expression, which is consistent with the lack of an inflammatory response in these animals. However, when 8-week-old infected SCID mice were immunologically reconstituted, signs of focal pulmonary inflammation were observed, and levels of RANTES, MCP-1, lymphotactin, MIP-1alpha, MIP-1beta, and MIP-2 mRNAs were all significantly elevated. Chemokine mRNA abundance was elevated at day 10 postreconstitution (PR), was maximal at day 12 PR, and returned to baseline by day 22 PR. In situ hybridization demonstrated that during the peak of inflammation, RANTES gene expression was localized to sites of inflammatory cell infiltration and P. carinii infection. Thus, these observations indicate that chemokines play a role in the focal targeting of inflammatory cell recruitment to sites of P. carinii infection after the passive transfer of lymphocytes to the host.
Wright
T W
TW
Departments of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. Terry_Wright@urmc.rochester.edu
Johnston
C J
CJ
Harmsen
A G
AG
Finkelstein
J N
JN
D000818:Animals; D018925:Chemokines / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression / Q000276:immunology*; D007249:Inflammation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011010:Pneumocystis; D011020:Pneumonia, Pneumocystis / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics
D018925:Chemokines; D012333:RNA, Messenger