TNF- Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia 1 Anita W. Rijneveld, 2 * † Sandrine Florquin, ‡ Judith Branger,* † Peter Speelman, † Sander J. H. Van Deventer,* and Tom van der Poll* † To determine the role of IL-1 in the host defense against pneumonia, IL-1R type I-deficient (IL-1R / ) and wild-type (Wt) mice were intranasally inoculated with Streptococcus pneumoniae. Pneumonia resulted in elevated IL-1 and IL-1 mRNA and protein levels in the lungs. Survival rates did not differ between IL-1R / and Wt mice after inoculation with 5  10 4 or 2  10 5 CFU. At early time points (24 and 48 h) IL-1R / mice had 2-log more S. pneumoniae CFU in lungs than Wt mice; at 72 h bacterial outgrowth in lungs was similar in both groups. Upon histopathologic examination IL-1R / mice displayed a reduced capacity to form inflammatory infiltrates at 24 h after the induction of pneumonia. IL-1R / mice also had significantly less granulocyte influx in bronchoalveolar lavage fluid at 24 h after inoculation. Since TNF is known to enhance host defense during pneumonia, we determined the role of endogenous TNF in the early impairment and subsequent recovery of defense mechanisms in IL-1R / mice. All IL-1R / mice treated with anti-TNF rapidly died (no survivors (of 14 mice) after 4 days), while 10-day survival in IL-1R / mice (control Ab), Wt mice (anti-TNF), and Wt mice (control Ab) was 7 of 13, 3 of 14, and 12 of 13, respectively. These data suggest that TNF is more important for host defense against pneumococcal pneumonia than IL-1, and that the impaired early host defense in IL-1R / mice is compensated for by TNF at a later phase. The Journal of Immunology, 2001, 167: 5240 –5246. C ommunity-acquired pneumonia caused by Streptococcus pneumoniae remains a major cause of morbidity and mortality, especially in the elderly (1, 2). The emergence and spread of penicillin-resistant S. pneumoniae have become a worldwide problem (3–5). Therefore, to develop novel therapeutic strategies it is crucial to study the host response during pneumonia caused by S. pneumoniae. Activation of the cytokine network plays an important role in the early response to severe infection (6). In models of systemic infection TNF is the first cytokine that becomes detectable in the circulation, followed shortly thereafter by IL-1 (7–9). TNF and IL-1 have highly overlapping biological activities and synergize in inducing systemic toxicity in animals in vivo (10, 11). Elimi- nation of either TNF or IL-1 activity during severe bacteremia in baboons largely prevents lethality, suggesting that excessive sys- temic production of these cytokines is of pivotal importance for the development of organ injury during the sepsis syndrome (12, 13). However, evidence indicates that the local production of proin- flammatory cytokines is crucial for the clearance of bacterial in- fections from the lung. Indeed, passive immunization against TNF impairs host defense during pneumococcal, Legionella, and Kleb- siella pneumonia in mice (14 –16). The role of IL-1 during bacte- rial pneumonia is less well defined. IL-1 is a pleiotropic proinflammatory cytokine, mainly produced by mononuclear phagocytes, which affects nearly all cell types. The IL-1 family consists of three members, namely, IL-1, IL-1, and IL-1R antagonist (IL-1Ra) 3 (17, 18). IL-1 can bind to two receptors, IL-1R types I and II. Type I receptors are found on most cell types, whereas expression of type II receptors is limited to blood neutrophils, monocytes, bone marrow progenitor cells, and B lymphocytes. IL-1R type II is not able to transduce a signal and is therefore generally referred to as a decoy receptor (19, 20). The type I IL-1R has equal affinities for IL-1, IL-1, and IL-1Ra. After binding of IL-1 to IL-1R type I, IL-1-IL-1R type I forms a complex with the IL-1R accessory protein, which results in signal transduction and biological effects, including induction of an acute phase response to sterile inflammation, fever, and synthesis of other proinflammatory cytokines and chemokines, such as IL-6, TNF, and IL-8 (17, 21). To determine the role of IL-1 in the pathogenesis of pneumo- coccal pneumonia, IL-1R type I gene-deficient (IL-1R -/- ) mice were compared with wild-type (Wt) mice after induction of pneu- monia with S. pneumoniae (22). In addition, the possible interac- tion between endogenous IL-1 and TNF during pneumonia was evaluated by treatment of IL-1R -/- and Wt mice with a neutral- izing anti-TNF Ab. Materials and Methods Animals All experiments were approved by the institutional animal care and use committee of the Academic Medical Center (Amsterdam, The Nether- lands). IL-1R -/- mice back-crossed six times to a C57BL/6 background Departments of *Experimental Internal Medicine, † Infectious Diseases, Tropical Medicine, and AIDS, and ‡ Pathology, Academic Medical Center, University of Am- sterdam, Amsterdam, The Netherlands Received for publication July 18, 2000. Accepted for publication August 27, 2001. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by grants from the Dutch Association for Scientific Re- search (to A.W.R.) and the Royal Dutch Academy of Arts and Sciences (to T.v.d.P.). 2 Address correspondence and reprint requests to Dr. Anita W. Rijneveld, Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Uni- versity of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E- mail address: a.w.rijneveld@amc.uva.nl 3 Abbreviations used in this paper: IL-1Ra, IL-1R antagonist; BAL, bronchoalveolar lavage; BALF, BAL fluid; MIP, macrophage inflammatory protein; Wt, wild type. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00