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Recently, we found that IFN\u2010\u03b3 and interleukin 4 (IL 4) also synergistically enhance the antileishmanial potential of M\u03a6. In this report, evidence is provided that the synergism of IFN\u2010\u03b3 and IL 4 is based on the ability of the lymphokines to induce the endogenous production of TNF\u2010\u03b1. First, both IFN\u2010\u03b3 and IL 4 as single agents and in combination were potent inducers of TNF\u2010\u03b1 production by M\u03a6 infected with <jats:italic>L. major<\/jats:italic> amastigotes. Second, the synergistic effect of IFN\u2010\u03b3 and IL 4 on parasite killing by M\u03a6 strongly correlated with their synergistic effect on the release of TNF\u2010\u03b1. Third, the IFN\u2010\u03b3\/IL 4\u2010mediated parasite elimination was completely abrogated not only in the presence of antibodies to IFN\u2010\u03b3 and IL 4, but also with an antibody specific for TNF\u2010\u03b1. Consistent with the conclusion that endogenously produced TNF\u2010\u03b1 accounts for the synergism of IL 4 with IFN\u2010\u03b3 is the finding that N<jats:sup>\u03c9<\/jats:sup>\u2010monomethyl\u2010<jats:sc>L<\/jats:sc>\u2010arginine, an inhibitor of the <jats:sc>L<\/jats:sc>\u2010arginine\u2010dependent generation of microbicidal nitrogen intermediates, totally blocked the M\u03a6 activation induced by IFN\u2010\u03b3 combined with IL 4 as well as by IFN\u2010\u03b3 combined with TNF\u2010\u03b1. These results underline the complex interplay of cytokines derived from lymphocytes and M\u03a6 and the role of TNF\u2010\u03b1 as pivotal factor for the induction of antileishmanial effector functions.<\/jats:p>","DOI":"10.1002\/eji.1830210713","type":"journal-article","created":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T13:02:34Z","timestamp":1172754154000},"page":"1669-1675","source":"Crossref","is-referenced-by-count":40,"title":["Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogenous tumor necrosis factor\u2010\u03b1 production by macrophages is induced by the synergistic action of interferon (IFN)\u2010\u03b3 and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN\u2010\u03b3 and IL 4"],"prefix":"10.1002","volume":"21","author":[{"given":"Steffen","family":"Stenger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Werner","family":"Solbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"R\u00f6llinghoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Bogdan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,12,13]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.9.3666"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.07.040189.003205"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.30.2.523-530.1980"},{"key":"e_1_2_1_5_2","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1096\/fasebj.4.14.2172061","volume":"4","author":"Larrick J. 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