Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes

Abstract

Gene- and signal-specific adaptation/tolerance of blood leukocytes to lipopolysaccharide endotoxin (LPS) occurs during human and animal septicemia. These phenotypes can be modeled in vitro. LPS-TLR4-adapted human THP-1 promonocytic cells cross-adapt to lipoteichoic acid (LTA)-TLR2-induced IL-1β/TNF-α production, suggesting disruption of a common intracellular signaling event(s). A plausible explanation for homologous adaptation of TLR4 with heterologous adaptation of TLR2 is a persistent inactivation and degradation of IRAK1 following TLR4 activation. LTA stimulation of TLR2 also produces homologous adaptation of TLR2 with inactivation of IRAK1, but there is no detectable degradation of IRAK1. Strikingly, such LTA-adapted cells still respond to LPS stimulation of TLR4 with rapid activation and degradation of IRAK1, and robust IL-1β/TNFα production. Moreover, cells adapted to either LTA- or LPS-production of IL-1β/TNF-α normally produce soluble interleukin 1 receptor antagonist (sIL-1Ra) anti-inflammatory protein when stimulated by either agonist. We conclude that: (i) disruption of a unique TLR2 signaling component upstream of IRAK1, but downstream of TLR2 sensing, induces homologous adaptation to LTA; (ii) disruption of IRAK1 may induce homologous adaptation of TLR4 to LPS and cross-adaptation of TLR2 to LTA; and (iii) TLR2/TLR4 signaling events that control sIL-1Ra translation do not adapt to LPS or LTA, indicating that TLR4 and TLR2 can still function. We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly.

References

Beutler B. , Poltorak A. The sole gateway to endotoxin response: how LPS was identified as TLR4, and its role in innate immunity. Drug Metab Dispos 2001; 29: 474—478.

Wagner H. Toll meets bacterial CpG-DNA. Immunity 2001 ; 14: 499—502.

Galanos C. , Gumenscheimer M. , Muhlradt P. , Jirillo E. , Freudenberg M.

MALP-2, a Mycoplasma lipopeptide with classical endotoxic properties: end of an era of LPS monopoly?

J Endotoxin Res 2000; 6: 471—476.

Angus DC , Wax RS Epidemiology of sepsis: an update. Crit Care Med 2001; 29: S109-S116.

Yoza BK , Hu JY , Cousart SL , McCall CE. Endotoxin inducible transcription is repressed in endotoxin tolerant cells. Shock 2000; 13: 236—243.

Baeuerle PA , Baltimore D. NF-kappa B: ten years after. Cell 1996; 87: 13—20.

Karin M. , Chang L. AP-1—glucocorticoid receptor crosstalk taken to a higher level. J Endocrinol 2001; 169: 447—451.

Learn CA , Mizel SB , McCall CE mRNA and protein stability regulate the differential expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells. J Biol Chem 2000; 275: 12185—12193.

Learn CA , Boger MS , Li L. , McCall CE. The phosphatidylinositol 3-kinase pathway selectively controls sIL-1Ra not interleukin-1beta production in the septic leukocytes. J Biol Chem 2001; 276: 20234—20239.

10.

Wang H. , Yang H. , Czura CJ , Sama AE , Tracey KJ HMG-1B1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med 2001; 164: 1768—1773.

11.

Martin TR MIF mediation of sepsis. Nat Med 2000; 6: 140—141.

12.

Calandra T. , Bucala R. Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system. Crit Rev Immunol 1997; 17: 77—88.

13.

Mueller LP , Yoza BK , Neuhaus K. et al. Endotoxin-adapted septic shock leukocytes selectively alter production of sIL-1Ra and IL-1beta. Shock 2001; 16: 430—437.

14.

McCall CE , Grosso-Wilmoth LM , LaRue K. , Guzman RN , Cousart SL Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome. J Clin Invest 1993; 91: 853—861.

15.

LaRue KE , McCall CE A labile transcriptional repressor modulates endotoxin tolerance. J Exp Med 1994; 180: 2269—2275.

16.

Jacinto R. , Hartung T. , McCall CE , Li L. Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance: distinct alterations in IL-1 receptor-associated kinase. J Immunol 2002; 168: 6136—6141.

17.

Lehner MD , Morath S. , Michelsen KS , Schumann RR , Hartung T. Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators . J Immunol 2001; 166: 5161—5167.

18.

Li L. , Cousart S. , Hu J. , McCall CE Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J Biol Chem 2000 ; 275: 23340—23345.

19.

Hu J. , Jacinto R. , McCall CE , Li L. Regulation of IL-1 receptor-associated kinases by lipopolysaccharide. J Immunol 2002; 168: 3910—3914.

20.

Li S. , Strelow A. , Fontana EJ , Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAKkinase . Proc Natl Acad Sci USA 2002; 99: 5567—5572.

21.

Ferlito M. , Romanenko OG , Ashton S. , Squadrito F. , Halushka PV , Cook JA Effect of cross-tolerance between endotoxin and TNFalpha or IL-1beta on cellular signaling and mediator production. J Leukoc Biol 2001; 70: 821—829.

22.

Zhang G. , Ghosh S. Negative regulation of Toll-like receptor-mediated signaling by TOLLIP. J Biol Chem 2002; 277: 7059—7065.

23.

Adib-Conquy M. , Cavaillon JM IFN-γ and GM-CSF prevent endotoxin tolerance in human monocytes by promoting IRAK expression and its association to MyD88, and not by modulating TLR4 expression. J Biol Chem 2002; In press.

24.

Mizel SB , Snipes JA Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from Toll-like receptor 5. J Biol Chem 2002; 277: 22414—22420.

25.

Kawasaki K. , Akashi S. , Shimazu R. , Yoshida T, Miyake K, Nishijima M. Mouse Toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 2000; 275: 2251—2254.

26.

Bauer S. , Kirschning CJ , Hacker H. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA 2001; 98: 9237—9242.

27.

Nomura F. , Akashi S. , Sakao Y. et al. Endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface Toll-like receptor 4 expression. J Immunol 2000; 164: 3476—3479.

28.

Medvedev AE , Henneke P. , Schromm A. et al. Induction of tolerance to lipopolysaccharide and mycobacterial components in Chinese hamster ovary/CD14 cells is not affected by overexpression of Toll-like receptors 2 or 4. J Immunol 2001; 167: 2257—2267.

29.

Suzuki N. , Suzuki S. , Duncan GS et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002; 416: 750—756.

30.

Swantek JL , Tsen MF , Cobb MH , Thomas JA IL-1 receptor-associated kinase modulates host responsiveness to endotoxin . J Immunol 2000; 164: 4301—4306.

31.

Horng T. , Barton GM , Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2001; 2: 835—841.

32.

Fitzgerald KA , Palsson-McDermott EM , Bowie AG et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001; 413: 78—83.

33.

Roger T. , Glauser MP , Calandra T. Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria. J Endotoxin Res 2001; 7: 456—460.

34.

Andersson U. , Wang H. , Palmblad K. et al. High mobility group 1 protein (HMG-1-1) stimulates pro-inflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565—570.