Macrophage effector functions controlled by Bruton's tyrosine kinase are more crucial than the cytokine balance of T cell responses for microfilarial clearance.
Macrophages from X-linked immunodeficient (xid) mice lacking functional Bruton's tyrosine kinase (Btk) show poor NO induction and enhanced IL-12 induction, and contribute to delayed clearance of injected microfilaria (mf) in vivo. We now show that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines (TNF-alpha, IL-1beta), but not the T cell-directed cytokine IL-12. Induction of some transcriptional regulators of the NF-kappaB family, crucial for the expression of proinflammatory cytokines, is also poor in Btk-deficient macrophages. Thus, Btk appears to be involved in signaling for inducible effector functions, but not APC functions, in macrophages. Furthermore, adoptive transfer of T cells from mf-infected xid or wild-type mice did not alter the course of mf clearance in recipients, mf clearance was unaltered in IFN-gamma-deficient mice, and improved mf clearance was seen only if greater inducibility of IL-12 was accompanied by greater NO secretion from macrophages, as seen in Ity(r) C.D2 mice as compared with congenic Ity(s) BALB/c mice. Thus, delayed mf clearance in xid mice was correlated not with the high IL-12/Th1 phenotype but with low NO induction levels. Also, xid macrophages showed poor toxicity to mf in vitro as compared with wild-type macrophages. Inhibition of NO production blocked this mf cytotoxicity, and an NF-kappaB inhibitor blocked both NO induction and mf cytotoxicity. Thus, Btk is involved in inducing many macrophage effector functions, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity.
Mukhopadhyay
Sangita
S
National Institute of Immunology, New Delhi, India.
Mohanty
Madhuchhanda
M
Mangla
Anita
A
George
Anna
A
Bal
Vineeta
V
Rath
Satyajit
S
Ravindran
Balachandran
B
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005368:Filariasis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008842:Microfilariae / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D009569:Nitric Oxide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse