Since the alveolar macrophages are first line of defense against of the respiratory tract pathogens study of factors produced by these cells may improve our understanding of the pathogenesis of infection and mechanisms of immunity. In the present study we investigated the nature and levels of cytokines produced by human respiratory tract cells in response to influenza virus infection. We studied several recent H1N1 and H3N2 wt viruses as well as reassortant ca vaccine viruses generated from A/Leningrad/134/17/57 (H2N2) MDS to understand how cold adaptation of virus may influence cytokine production. We have shown that in general H3N2 viruses are greater inducers of proinflammatory cytokines compared with H1N1 influenza A viruses. That can explain the severity of infections and complications cause by H3N2 viruses. Cold-adapted reassortant viruses produced the cytokines levels similar to that of wt parents at high MOI, but at lower MOI, ca reassortant viruses were less efficient in inducing of cytokines compared with wt viruses. The study of SGR's viruses bearing one of mutated gene from Len/17 MDS demonstrated that the polymerase genes were critical for infection and cytokine production in human macrophages since reassortants bearing the polymerase genes from the ca virus induced lower levels of cytokines in human macrophages, whereas viruses bearing the M or NS genes from the ca virus did not. Further studies of proinflammatory cytokine responses induced by wt and ca reassortant strains may provide a rational basis for the selection of ca vaccine candidates with improved immunogenicity for humans. © 2006 Elsevier Ltd. All rights reserved.